Advertisement
Research ArticleMinireview—A Latin American Perspective On G Protein-Coupled Receptors

Current Knowledge and Perspectives on Histamine H1 and H2 Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

Federico Monczor and Natalia Fernandez
Molecular Pharmacology November 2016, 90 (5) 640-648; DOI: https://doi.org/10.1124/mol.116.105981

Abstract

H1 and H2 histamine receptor antagonists, although developed many decades ago, are still effective for the treatment of allergic and gastric acid–related conditions. This article focuses on novel aspects of the pharmacology and molecular mechanisms of histamine receptors that should be contemplated for optimizing current therapies, repositioning histaminergic ligands for new therapeutic uses, or even including agonists of the histaminergic system in the treatment of different pathologies such as leukemia or neurodegenerative disorders. In recent years, new signaling phenomena related to H1 and H2 receptors have been described that make them suitable for novel therapeutic approaches. Crosstalk between histamine receptors and other membrane or nuclear receptors can be envisaged as a way to modulate other signaling pathways and to potentiate the efficacy of drugs acting on different receptors. Likewise, biased signaling at histamine receptors seems to be a pharmacological feature that can be exploited to investigate nontraditional therapeutic uses for H1 and H2 biased agonists in malignancies such as acute myeloid leukemia and to avoid undesired side effects when used in standard treatments. It is hoped that the molecular mechanisms discussed in this review contribute to a better understanding of the different aspects involved in histamine receptor pharmacology, which in turn will contribute to increased drug efficacy, avoidance of adverse effects, or repositioning of histaminergic ligands.

Introduction

Histamine is a biogenic amine that exerts its physiologic action by binding to receptors belonging to the superfamily of seven transmembrane G protein–coupled receptors (GPCRs). To date, four different types of histamine receptors have been described: H1R, H2R, H3R, and H4R (Panula et al., 2015).

Most of the studies carried out in the last twenty years were mainly focused on the newly described H3R and H4R, whereas H1R and H2R were originally characterized many years ago. To date, H1R and H2R are the only histamine receptors for which drugs have been approved for use in humans. H1R and H2R are still effective targets for the treatment of allergies and some forms of gastric acid–related conditions, and H1R and H2R antagonists belong to the top 18 drug classes used between 1999 and 2012 (Simons and Simons 2011; Kantor et al., 2015; Iwakiri et al., 2016).

The pharmacology of histamine receptors was comprehensively reviewed in numerous excellent articles published recently (Panula et al., 2015; Haas and Panula, 2016). However, based on the enormous costs for developing new drugs, this review aims to discuss the different aspects of histamine receptor function that have been characterized more recently and can be considered for repositioning histaminergic ligands for new therapeutic uses or for optimizing the usage of these existing ligands (Nosengo, 2016). Here, we provide an exhaustive review of novel or potential applications of old histaminergic drugs as well as the potential therapeutic implications of functional ligand selectivity and crosstalk.

H1R and H2R Signaling

H1R canonical signaling involves activation of the Gq/11 protein and its effector phospholipase C (PLC), with a consequent increase in inositol phosphates (IPs) and intracellular calcium levels in most systems, as well as the activation of small G proteins Rac and RhoA (Gutowski et al., 1991; Notcovich et al., 2010). Alternatively, in native and heterologous H1R expression systems, H1R signaling via Gi/o, phospholipase A2 activation, and cGMP and nitric oxide production has been described (Richelson, 1978; Snider et al., 1984; Leurs et al., 1994; Seifert et al., 1994; Wang and Kotlikoff, 2000; Prast and Philippu, 2001). In the mammalian brain, adrenal glands, and Chinese hamster ovary cells, activation of H1R may also stimulate adenylyl cyclase (AC) with consequent intracellular cAMP production (Keogh and Marley, 1991; Marley et al., 1991). Aside from the signaling events triggered by ligand binding, H1R was shown to display high levels of spontaneous receptor activity in the absence of agonists. H1R was also shown to constitutively activate both IP production and modulation of gene expression under the control of nuclear factor-κB (Bakker et al., 2001; Fitzsimons et al., 2004). On the basis of these observations, all clinically relevant H1R ligands were reclassified as H1R inverse agonists (Bakker et al., 2000). However, since all marketed antihistamines are actually inverse agonists, it cannot be determined whether this pharmacological property is therapeutically more relevant than neutral antagonism or histamine receptor blockade.

In most tissues where H2R is expressed, H2R couples to Gs protein and its activation stimulates AC-mediated cAMP production (Alewijnse et al., 1998; Monczor et al., 2003; Panula et al., 2015). The coupling of H2R to Gs proteins was demonstrated by agonist-induced photoaffinity-labeling studies with GPCR-Gαs fusion proteins, guanosine 5′-O-(3-[35S]thio)triphosphate binding, as well as steady-state GTP hydrolysis (Leopoldt et al., 1997; Kelley et al., 2001; Wenzel-Seifert et al., 2001). H2R displayed lower affinity for histamine than the H3 and H4 subtypes and had high constitutive activity toward cAMP production (Panula et al., 2015).

In some H2R native or heterologously expressing cells, H2R can also couple to Gq/11 proteins in addition to the classic signaling through Gs protein, leading to IP synthesis and a consequent increase in intracellular Ca2+ concentration (Panula et al., 2015). H2R stimulation by histamine was shown to potently inhibit phospholipase A2 activity, triggering arachidonic acid synthesis (Traiffort et al., 1992). Interestingly, some actions mediated by H2R, such as modulation of cell proliferation and gene expression, are shown to involve the modulation of signaling cascades that are usually associated with tyrosine kinase receptors, such as the extracellular signal-regulated kinase (ERK1/2) or phosphoinositide 3-kinase pathway (Leopoldt et al., 1997; Mettler et al., 2007; Bonini et al., 2011; Luo et al., 2013; Alonso et al., 2016). In addition, histamine or H2R agonists inhibit the activity of NADPH oxidase, the enzyme responsible for the generation of reactive oxygen species (ROS), in myeloid cells (Aurelius et al., 2012).

All H2R antagonists that are used clinically, including cimetidine, famotidine, and ranitidine, behave as inverse agonists (Smit et al., 1996; Monczor et al., 1998). However, as with H1R ligands, whether inverse agonism is relevant for their therapeutic action remains to be elucidated.

Studies have shown that G protein–coupled receptor kinase (GRK)-2 is the principal kinase that participates in both H1R and H2R desensitization after long-lasting or repetitive stimulation. Besides receptor phosphorylation by GRK-2, H1R and H2R desensitization also involves the inactivating action of the regulator of G protein signaling domain of GRK-2 over the G proteins (Shayo et al., 2001; Fernández et al., 2002; Iwata et al., 2005; Fernandez et al., 2011). After GRK-mediated phosphorylation, receptors are internalized in clathrin-coated pits by a mechanism dependent of arrestin and/or dynamin action and they are recycled back to the cell surface or degraded in lysosomes (Fernandez et al., 2008; Hishinuma et al., 2010).

Although H1R and H2R were the first to be characterized, they continue to demonstrate unique signaling complexities that may account for their effects on biologic systems and may provide the basis for yet-unexplored therapeutic strategies. In the following sections, we discuss more recently described features of the signaling molecular mechanisms of H1R and H2R and their potential therapeutic implications.

Biased Signaling at H1 and H2 Histamine Receptors

Growing evidence shows that the multiplicity of signaling events associated with a unique GPCR leads to the identification of ligands that bind the receptor and then favor some specific signaling events among the texture of receptor possibilities. A critical assumption is that the heterogeneity of active receptor conformations spontaneously exists and the ligand stabilizes a particular conformational subset that fails to evoke some of the responses but may stimulate other signaling events of the receptor to which it binds (Kenakin, 2004; Rajagopal et al., 2010). This process of “stimulus trafficking” has also been referred to as biased agonism or functional selectivity, and it explains why a ligand causes differential activation of only some of the signaling pathways associated with a specific receptor (Pupo et al., 2016).

This pluridimensional aspect of efficacy was extensively studied for the adrenergic receptors (Galandrin and Bouvier, 2006) and the angiotensin II receptor (Wei et al., 2003). Prior studies demonstrate that biased agonism is a phenomenon that also occurs for several GPCRs including H1R and H2R in native and recombinant systems (Moniri et al., 2004; Reher et al., 2012a; Alonso et al., 2014, 2015).

Biased Signaling for H1R Ligands.

The discovery of agonists acting at H1R has been disregarded for a long time and efforts were focused on the development of ligands that block the H1R-mediated histamine allergic action. Although histamine possesses several physiologic and pathophysiologic effects acting at H1R, a therapeutic use for H1R agonists has not yet been found. However, one of the seminal studies providing experimental evidence to underpin the concept of biased agonism was performed at H1R. Two H1R ligands of the same class that mainly differed with regard to stereochemistry, cis-PAB [(6)-cis-5-phenyl-7-dimethylamino-5,6,7,8-tetrahydro-9H- benzocycloheptane] and trans-PAT [(2)-trans-1-phenyl-3- dimethylamino-1,2,3,4-tetrahydronaphthalene, displayed functional heterogeneity at modulating the PLC/IP versus AC/cAMP signaling pathways of H1R. Whereas PAB presented partial agonism at activating the PLC/IP cascade and no efficacy at the AC/cAMP pathway, PAT behaved oppositely by stimulating cAMP production and blocking IP formation (Moniri and Booth, 2004; Moniri et al., 2004). cAMP production after endogenous histamine stimulation of H1R leads to the activation of tyrosine hydroxylase (the enzyme responsible for l-dopa synthesis), the precursor of dopamine, noradrenaline, and adrenaline. Moniri and Booth (2006) reported that this differential activation of AC/cAMP and consequently tyrosine hydroxylase by H1R ligands in mammalian brain and adrenal tissues could have implications in the treatment of several neurodegenerative disorders, as further discussed below.

Biased Signaling for H2R Ligands.

As mentioned previously, H2R blockers used in the clinic for treatment of gastric acid–related disorders (e.g., cimetidine, famotidine, and ranitidine) are well known inverse agonists regarding cAMP production (Smit et al., 1996; Monczor et al., 1998). Interestingly, although they diminish cAMP production, all of these ligands (as well as tiotidine, the classic reference ligand used in research) behave as full agonists with regard to H2R desensitization and internalization. Although the extent and rate of H2R internalization induced by inverse agonists was similar to that of agonist-promoted endocytosis, it was independent of GRK-2–mediated phosphorylation. Moreover, the protein partner profile and receptor fate of H2R once it is endocytosed are strikingly different when desensitization/internalization processes are triggered by agonists or inverse agonists (Alonso et al., 2014). However, cimetidine, famotidine, ranitidine, and tiotidine also present a biased profile toward activation of the ERK1/2 signaling pathway over cAMP production. Again, although inverse agonists and histamine or H2R agonists have positive efficacy in increasing ERK1/2 phosphorylation, the underlying mechanisms are different. H2R agonist-stimulated ERK1/2 phosphorylation is mediated by dynamin, whereas cimetidine, ranitidine, and tiotidine lead to an increase in phospho-ERK levels by a mechanism that is independent of dynamin or even H2R internalization but is mediated by Gβγ (Xu et al., 2008; Alonso et al., 2014, 2016). Notably, ERK1/2 modulation is involved in the regulation of histidine decarboxylase (HDC) expression, the enzyme responsible for histamine synthesis (Colucci et al., 2001).

Biased agonism has also been described for H2R in neutrophils and eosinophils. These cells are chemoattracted and migrate to the focus of infection, releasing a variety of cytotoxic enzymes, cytokines, and ROS playing a pivotal role in host defense against microbes and viruses (Pincus et al., 1982; Burde et al., 1989; Adamko et al., 2002; Rothenberg and Hogan, 2006; Soehnlein et al., 2009; Sadik et al., 2011; Reher et al., 2012b). H2R activation results in inhibition of granulocyte superoxide release (Gespach and Abita, 1982; Burde et al., 1989; Ezeamuzie and Philips, 2000). Although cAMP increments are related to inhibition of ROS release, substantial evidence has shown that H2R agonists dimaprit and impromidine are biased ligands toward ROS inhibition over cAMP production in neutrophils and eosinophils (Reher et al., 2012a). Given the use of histamine-mediated inhibition of ROS release for the treatment of acute myeloid leukemia (AML) (Aurelius et al., 2012), this ligand bias could be of great value in the clinic, as further discussed below.

Histaminergic Regulation of the Signaling of Other Receptors

Considerable progress in biochemistry and molecular biology in recent years has led to significant changes in how cellular signaling is studied and how the experimental results are interpreted. Traditionally, studies focused on outlining direct upstream and downstream interactions as linear paths that transmit information from the cell environment to intracellular effectors, through receptors (Weng et al., 1999). Holistic analyses of signaling pathways in cell systems revealed that signals do not necessarily disseminate in a linear manner. Alternatively, cellular signaling networks are composed of modules that cannot be considered as isolated entities and that regulate multiple functions integrating the information the cell receives from the environment, producing a unified response dependent of the context (Jordan et al., 2000; Bockaert et al., 2003; Di Roberto et al., 2016).

H1R and H2R Interfere in the Activity of Other GPCRs.

Several ways in which GPCRs functionally interact with other pathways have been described. In particular, some inverse agonists of histamine receptors are shown to interfere with the response of other GPCRs that share the same signaling pathway. For example, tiotidine, after binding to H2R, impairs the signaling of other Gs-coupled GPCRs such as the β-adrenergic, calcitonin, and prostaglandin E2 receptors (Monczor et al., 2003; Tubio et al., 2010). Furthermore, the mere overexpression of H2R interferes with the signaling of these GPCRs and H2R knockdown potentiates their response (Tubio et al., 2010). In the same way, mepyramine binding to H1R interferes with the signaling of the Gq-coupled ATP receptor. These ligands are thought to stabilize a conformation of the receptor that (although inactive) may couple and recruit G protein, making it less available for other unrelated receptors that signal through the same pathway (Fig. 1, top). This interpretation also explains why the phenomenon of interference is no longer observed after G-protein overexpression (Fitzsimons et al., 2004; Tubio et al., 2010).

Fig. 1.
Fig. 1.

Mechanisms of crosstalk mediated by H1R and H2R and their potential implications in therapy. (Top) Inverse agonists acting at H1R or H2R promote receptor binding to G protein in an inactive form, making it less available to other GPCRs that signal through the same pathway. (Middle) Antihistamines acting at H1R potentiate dexamethasone-induced GR transcriptional activity. (Bottom) H1R and H2R crossdesensitize when stimulated with either H1 or H2 agonists. The molecular mechanisms underlying the described effects are detailed in the main text.

H1R and H2R Crossregulation.

H1R and H2R are coexpressed in most cell types, such as neurons, granulocytes, lymphocytes, monocytes/macrophages, dendritic cells, endothelial and epithelial cells, and airway and vascular smooth muscle cells (Parsons and Ganellin, 2006; Jutel et al., 2009). In these systems, the action of endogenous histamine may result from the balance and coordination of the signaling events activated by the H1R and H2R histamine receptor subtypes (or even others).

H1R and H2R crossregulation has been described. In recombinant and native systems, both receptors were desensitized when cells were exposed to a sustained stimulus with any H1R or H2R agonist (Alonso et al., 2013). This crossdesensitization occurs by a mechanism that is not dependent of second messengers and their kinases. Fluorescence resonance energy transfer assays revealed that after activation of H1R and H2R, the receptors colocalize in endosomes forming heteromers. Hence, negative histamine receptor crossregulation results, having physiologic consequences, conditioning the extent of cell proliferation or cell death after receptor stimulation (Alonso et al., 2013). This observation indicates that the biologic output after H1R or H2R stimulation is conditioned or even dampened by this mechanism (Fig. 1, middle).

H1R and H2R Modulation of Nuclear Receptor Activity.

Crosstalk between signals triggered by membrane receptors has been widely studied and described. On the contrary, modulation of nuclear receptor activity by GPCRs is much less documented. However, some studies have explored the possibility of regulating the transcriptional activity of glucocorticoid receptors (GRs) through the modulation of GPCR-mediated signaling. Adrenaline and noradrenaline acting on β2-adrenergic receptors enhance GR activity via a Gβγ/phosphoinositide 3-kinase/protein kinase B pathway (Schmidt et al., 2001). Yet somatostatin and melatonin receptor activation suppresses GR activity through Gβγ and Gαi proteins, respectively (Kiefer et al., 2005; Kino et al., 2005).

Despite the common therapeutic association between GR agonists and antihistaminergic ligands, few studies have been conducted to characterize the effects of H1R signaling on GR activity. Investigators recently observed that histamine, as well as antihistamines, are able to potentiate GR activity (Zappia et al., 2015). When H1R is stimulated by histamine, a complex dual process triggers. On the one hand, Gαq/PLC signaling inhibits the GR response to dexamethasone. On the other hand, the Gβγ dimer enhances the GR response to dexamethasone through Jun kinase–mediated phosphorylation of the receptor. The balance of both regulatory pathways results in the activation of GR activity. However, since H1R inverse agonists potently inhibit Gαq/PLC signaling, they also lead to potentiation of the GR response to dexamethasone (Fig. 1, bottom) (Zappia et al., 2015). This potentiating effect of histamine and antihistamines on GR activity is shown to alter the expression of endogenous genes transactivated and transrepressed by dexamethasone and related to inflammatory processes (Zappia et al., 2015). This somehow paradoxical effect, in which antihistamines actually behave as partial agonists concerning GR activity, has profound clinical consequences as we further discuss below. Table 1 summarizes the above information regarding histamine receptor signaling.

View this table:
TABLE 1

Histamine H1R and H2R: signaling pathways, receptor crosstalk, and ligands

Pharmacology of H1 and H2 Histamine Receptors: From Classic Uses to Repurposing and Novel Indications

Classic Clinical Uses of Histaminergic Ligands.

Antihistamines have a well established place in the treatment of diverse allergic situations, including anaphylactic shock, and are promptly available as prescription and over-the-counter drugs. Therapeutically relevant H1R drugs are inverse agonists: loratadine, azelastine, fexofenadine, desloratadine, levocetirizine, cetirizine, and olopatadine. These ligands are widely used in the treatment of hay fever, allergic rhinitis and conjunctivitis, and hives (Simons and Simons, 2011). Antihistamines have been also formulated for local application to the mucosa or skin, diminishing the symptoms caused by localized or systemic histamine (Ostrom, 2014; Solelhac and Charpin, 2014).

H2R antagonists cimetidine, ranitidine, nizatidine, and famotidine are classic treatments for patients presenting gastric or duodenal ulcers, dyspepsia, or gastroesophageal reflux disease (Hershcovici and Fass, 2011; Sigterman et al., 2013). Antibiotic therapies for Helicobacter infections and the discovery of proton pump inhibitors have overtaken the antisecretory H2R antagonists for gastroesophageal symptomatic treatment (Marshall and Warren, 1984; Marshall et al., 1988; Olbe et al., 2003). However, there has been a renaissance in the use of H2R antagonists to prevent gastrointestinal ulcers among patients taking nonsteroidal anti-inflammatory drugs (Koch et al., 1996; Rostom et al., 2002). For example, a combination of ibuprofen and the H2R antagonist famotidine (DUEXIS; Horizon Pharma, Lake Forest, IL) is available for the treatment of arthritis (Laine et al., 2012).

On the basis of these findings and taking into account the more recently described functional selectivity and crosstalk of H2R, it is necessary to consider these phenomena in the context of the clinical use of H2R blockers. The inhibition of gastric acid secretion is achieved by blocking the canonical AC/cAMP signaling pathway of H2R. However, some H2R inverse agonists are shown to increase phospho-ERK levels mimicking the effects of histamine (Alonso et al., 2015). As mentioned previously, ERK activation induces the expression of HDC, the enzyme that synthesizes histamine, potentially increasing the synthesis of the ligand that it is supposed to antagonize (Alonso et al., 2016). Moreover, long-term H2R blockade increases the parietal cell response to histamine and leads to tolerance to treatment with H2 antagonists. This is explained by an increase in receptor membrane expression due to structural stabilization of H2R by the inverse agonists (Smit et al., 1996). However, the induction of HDC expression by famotidine can be an additional explanation regarding the undesired rebound effects of H2R blockers, and it may also explain why these ligands produce increased hypersecretion of gastric acid after withdrawal (Smith et al., 1999). If this is the case, an H2R neutral antagonist or inverse agonist that fails to induce HDC expression would avoid such undesired effects.

Although G protein scavenging by H1 or H2 inverse agonists was mentioned above, we could not find examples in the literature in which this phenomenon would be responsible for adverse effects or drug–drug interactions. However, these effects cannot be discarded a priori, since G protein scavenging has actual consequences on the response of other GPCRs that are coupled to the same signaling pathway.

Potential Repurposing of Classic H1R Ligands.

Despite the extensive study and clinical applications of histamine H1R and H2R pharmacology, there are novel and proposed uses for repositioning histaminergic ligands. Since 2011, the National Institutes of Health has augmented activities to facilitate repurposing of existing drugs (Huang et al., 2011). In this context, histaminergic ligands are low-cost drugs with very good, established safety profiles and no patent protection, which allows fast tracking for human trials.

Based on the recently described crosstalk between H1R signaling and GR activity, antihistaminic and antiallergic ligands could potentially be repositioned as adjuvants for corticoid therapies to diminish the adverse effects of corticoids. As mentioned above, H1R inverse agonists are able to modulate GR transcriptional activity by potentiating transactivation and transrepression of key genes in the inflammatory response (Zappia et al., 2015). The existence of relevant cell types coexpressing both receptors, such as endothelial cells, dendritic cells, monocytes, neutrophils, T and B cells, and microglia, suggests that this interaction may have implications for the regulation of inflammation in several systems (Lu et al., 2006; Panula et al., 2015). In the search for strategies to improve the beneficial/undesired effect ratio in the clinical administration of glucocorticoids, add-on therapies have had very good results. These therapies consist of the combination of corticoids with other drugs that potentiate corticoid effects by a different mechanism of action, thereby decreasing the dose of corticoid administered as well as diminishing its adverse effects. By this approximation, corticoids have been used in combination with β2-adrenoreceptor agonists (e.g., theophylline) or with leukotriene receptor antagonists (e.g., montelukast) to treat asthma (Louis et al., 2012). In this regard, combination therapy with glucocorticoids and antihistamines may not only be beneficial for patients with concomitant allergic and inflammatory processes, but the antihistamine-potentiating effects of such therapy may also allow a reduction in corticoid doses.

In support of this hypothesis, the antihistamine olopatadine was shown in vivo to enhance prednisolone inhibition of scratching and skin symptoms in an atopic dermatitis murine model (Kagawa et al., 2010). Likewise, H1R blocker azelastine reduced the frequency of administration of inhaled corticosteroids without loss of pulmonary function in a clinical trial with patients with chronic asthma (Busse et al., 1996).

Repositioning of antihistaminergic ligands is also proposed by taking advantage of the generalized actions that are mediated by histamine throughout the body and the ubiquitous expression of H1R. Novel clinical applications for these ligands are being investigated, with different degrees of success.

The action of H1R in the central nervous system was originally seen as an undesired action of antihistamines due to sedative effects of first-generation antiallergic drugs. However, new approaches rely on histamine H1R central expression. Histamine has been implicated in pain modulation, augmenting the transmission of nociceptive impulses; considerable evidence indicates that several H1 blockers are indeed analgesic agents (McHugh and McHugh, 2000; Mobarakeh et al., 2000; Sakurada et al., 2004). Recent data indicate that cetirizine potentiates the analgesic and antiedematogenic effects of morphine (Stein et al., 2016), suggesting an unexplored use for classic antihistamines in pain relief.

H1R antagonists are also proposed to be beneficial in the treatment of neurodegenerative disorders that have a neuroinflammatory component, such as Parkinson disease and amyotrophic lateral sclerosis (Dong et al., 2014; Rocha et al., 2014). Chronic treatment with clemastine enhances neuronal survival and modulates the expression of inflammatory genes in microglia (Apolloni et al., 2016). Furthermore, it has been suggested that the blockade of histamine-induced dopaminergic neuronal toxicity would improve neuronal protection, with potential clinical applications for Parkinson disease (Rocha et al., 2016).

Histaminergic neurons are active during wakefulness and are inhibited during rapid eye movement sleep by GABAergic neurons located in the hypothalamus (Shan et al., 2015). On that basis, antihistamines with central action (e.g., diphenhydramine and doxylamine) are widely used for insomnia therapy, although their use is not recommended for long periods due to rapidly developed tolerance (Krystal, 2015). The U.S. Food and Drug Administration approved the antihistamine doxepin for the “treatment of insomnia characterized by difficulties with sleep maintenance” (Neubauer, 2014), which is consistent with published data indicating that antihistamines have greater effects on sleep maintenance than on sleep onset (Morin et al., 2005; Glass et al., 2008). Although concerns have been raised regarding the degree to which these properties reflect specific H1R antagonism or nonspecific action over muscarinic M1 receptors, this possibility has been ruled out by the observation that low doses of doxepin (that act solely on H1R) show a significant improvement in total sleep time and efficiency with no evidence of morning residual impairment or sedation (Scharf et al., 2008; Krystal et al., 2011; Krystal, 2015)

Potential Repurposing of Classic H2R Ligands.

In addition to H2R’s classic regulation of gastric acid secretion, H2R signaling has also been implicated in the development of cardiovascular disease. High concentrations of histamine are found in cardiac tissues and the positive inotropic effects mediated by H2R stimulation may be important in the pathophysiology of cardiovascular disease (Eckel et al., 1982; Kirch et al., 1992; Hattori, 1999; Shi et al., 2015). In fact, the blocking of histamine release or H2R antagonism prevented heart failure in rabbits with doxorubicin-induced cardiomyopathy and dogs with sustained atrial tachycardia (Takahama et al., 2010). In addition, H2R−/− knockout mice had resistance to heart failure and had lower levels of cardiac fibrosis when subjected to transverse aortic constriction (Zeng et al., 2014). Although there is no current evidence supporting this, it would be interesting to determine whether the cardioprotective action of H2R blockers relies, at least partially, on decreased responsiveness of the β-adrenoreceptor due to scavenging of Gαs protein by H2R. In a prospective study conducted in a cohort from the Multi-Ethnic Study of Atherosclerosis with more than 6000 cases, Leary et al. (2016) concluded that the use of H2R antagonists prevented the onset of chronic heart failure. On the basis of this evidence, H2R ligands are being repurposed as reliable drugs to provide benefits to patients with chronic heart failure.

In addition to these attempts to reposition classic histaminergic ligands, they are also being considered for improving diabetic conditions and treating infections and cancer (for review, see Deva and Jameson, 2012; Pantziarka et al., 2014; Pini et al., 2016).

Biased Signaling and Novel Drugs of the Classic Histaminergic System.

Several drugs marketed worldwide act on receptors that demonstrate biased agonism (Kenakin and Miller, 2010). Although there is a clear theoretical advantage in this pharmacological complexity, there are currently no drugs approved for their use based on their biased therapeutic profiles (Kingwell, 2015). In general, biased ligands could surmount on-target undesirable events circumventing certain pathways, or they could enhance their therapeutic efficacy by avoiding or stimulating specific negative or positive feedback loops in their signaling pathways. The recent development of some new drugs has taken advantage of this signaling multiplicity of ligands with promising results (Violin et al., 2014).

This functional heterogeneity has been described for H1 and H2 histamine receptors as mentioned above. In the brain, histamine not only signals through the canonical Gq/calcium pathway by acting through the presynaptic H1R, but it also stimulates AC/cAMP signaling. Neuronal activation of the cAMP pathway leads to tyrosine hydroxylase activity and dopamine synthesis. Interestingly, this behavior, dependent of the AC/cAMP pathway, is conserved in trans-PAT biased agonism without stimulating the canonical calcium signaling that may account for histamine-mediated allergic responses and hyperalgesia (Galeotti et al., 2004; Moniri et al., 2004). This biased behavior may be of possible value in treating neurodegenerative or neuropsychiatric disorders involving dopamine synthesis.

H2R agonists have been also proposed as promising drugs for the inhibition of neutrophil and eosinophil function since they inhibit superoxide anion formation by these cell types (Reher et al., 2012a).

Histamine dihydrochloride (Ceplene; Immune Pharmaceuticals, New York, NY) has been approved for the treatment of patients suffering from AML, and H2R agonists are being extensively studied as promising drug candidates for the treatment of AML and inflammatory diseases (Burde et al., 1989, 1990; Jutel et al., 2009; Martner et al., 2010). By inhibiting ROS production, H2R ligands allow agents that stimulate the immune system (e.g., interleukin-2) to effectively activate cytotoxic cells, improving tumor cell death (Hellstrand, 2002). As a result, combined histamine and interleukin-2 postremission therapy was shown to significantly prevent AML relapse (Buyse et al., 2011; Aurelius et al., 2012).

As mentioned above, H2R agonists are reported to inhibit ROS generation in myeloid cells by a mechanism that is not mediated by cAMP accumulation. Indeed, dimaprit and impromidine were described as H2R biased agonists toward ROS inhibition in neutrophils and eosinophils (Reher et al., 2012a). These results suggest that H2R biased signaling toward the inhibition of ROS production may present a beneficial effect by allowing cytotoxic cells to kill leukemic cancer cells (Monczor et al., 2016). Table 2 summarizes the above-presented data concerning the current and potential clinical applications of histaminergic ligands.

View this table:
TABLE 2

Clinical uses of histaminergic ligands according to their molecular mechanisms of action: current, proposed, and nontraditional

Final Considerations

Getting a drug to market takes 13–15 years and costs between 2 and 3 billion dollars on average; repositioning a drug takes less than one-half of that time and costs almost one-tenth of this amount (Nosengo, 2016). Molecular pharmacology studies rely on the ultimate understanding of the effects of a given ligand on a biologic system that may account for its therapeutic utility. Although histaminergic ligands for H1R and H2R were described several decades ago, recently discovered signaling phenomena can be very useful to conceive novel therapeutic strategies or to optimize treatments already in use. In the same way, improved understanding of the complete picture of histamine actions may help to repurpose classic histaminergic low-cost ligands with novel therapeutic uses. In the attempt to understand the pharmacology of a ligand, there is always a risk regarding the election of the “experimental eyes” that are used to estimate its action and efficacy. The latter advances in physics, biology, and chemistry have been beneficial for the measurement of the ability of histaminergic ligands to produce a biologic response or to interfere in the response of other receptors, further enhancing knowledge even about the classic pharmacology of H1R and H2R. Although the basis of histaminergic clinical pharmacology goes back to the prototypical effects described long ago by Sir James Black (Black et al., 1972), it is hoped that the mechanistic aspects discussed in this review will improve understanding of the histaminergic system as well, helping to repurpose classic ligands of the histaminergic system, increase drug efficacy, and avoid adverse effects.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Monczor, Fernandez.

Footnotes

    • Received July 5, 2016.
    • Accepted September 12, 2016.

  • This research was supported by the Agencia Nacional de Promoción Científica y Tecnológica [Proyectos de Investigación Científica y Tecnológica nos. 495 and 2050].

  • dx.doi.org/10.1124/mol.116.105981.

Abbreviations

AC
adenylyl cyclase
AML
acute myeloid leukemia
ERK
extracellular signal-regulated kinase
GPCR
G protein–coupled receptor
GR
glucocorticoid receptor, GRK, G protein–coupled receptor kinase
HDC
histidine decarboxylase
IP
inositol phosphate
PAB
(6)-cis-5-phenyl-7-dimethylamino-5,6,7,8-tetrahydro-9H- benzocycloheptane
PAT
(2)-trans-1-phenyl-3- dimethylamino-1,2,3,4-tetrahydronaphthalene
PLC
phospholipase C
ROS
reactive oxygen species

References

  1. ↵
    1. Adamko D,
    2. Lacy P, and
    3. Moqbel R
    (2002) Mechanisms of eosinophil recruitment and activation. Curr Allergy Asthma Rep 2:107–116.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Alewijnse AE,
    2. Smit MJ,
    3. Hoffmann M,
    4. Verzijl D,
    5. Timmerman H, and
    6. Leurs R
    (1998) Constitutive activity and structural instability of the wild-type human H2 receptor. J Neurochem 71:799–807.
    OpenUrlPubMed
  3. ↵
    1. Alonso N,
    2. Diaz Nebreda A,
    3. Monczor F,
    4. Gutkind JS,
    5. Davio C,
    6. Fernandez N, and
    7. Shayo C
    (2016) PI3K pathway is involved in ERK signaling cascade activation by histamine H2R agonist in HEK293T cells. Biochim Biophys Acta 1860:1998–2007.
    OpenUrl
  4. ↵
    1. Alonso N,
    2. Fernandez N,
    3. Notcovich C,
    4. Monczor F,
    5. Simaan M,
    6. Baldi A,
    7. Gutkind JS,
    8. Davio C, and
    9. Shayo C
    (2013) Cross-desensitization and cointernalization of H1 and H2 histamine receptors reveal new insights into histamine signal integration. Mol Pharmacol 83:1087–1098.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Alonso N,
    2. Monczor F,
    3. Echeverría E,
    4. Davio C,
    5. Shayo C, and
    6. Fernández N
    (2014) Signal transduction mechanism of biased ligands at histamine H2 receptors. Biochem J 459:117–126.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Alonso N,
    2. Zappia CD,
    3. Cabrera M,
    4. Davio CA,
    5. Shayo C,
    6. Monczor F, and
    7. Fernández NC
    (2015) Physiological implications of biased signaling at histamine H2 receptors. Front Pharmacol 6:45.
    OpenUrl
  7. ↵
    1. Apolloni S,
    2. Fabbrizio P,
    3. Parisi C,
    4. Amadio S, and
    5. Volonté C
    (2016) Clemastine confers neuroprotection and induces an anti-inflammatory phenotype in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Mol Neurobiol 53:518–531.
    OpenUrlCrossRef
  8. ↵
    1. Aurelius J,
    2. Martner A,
    3. Brune M,
    4. Palmqvist L,
    5. Hansson M,
    6. Hellstrand K, and
    7. Thoren FB
    (2012) Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells. Haematologica 97:1904–1908.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Bakker RA,
    2. Schoonus SB,
    3. Smit MJ,
    4. Timmerman H, and
    5. Leurs R
    (2001) Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q/11)-subunits in constitutive and agonist-mediated signaling. Mol Pharmacol 60:1133–1142.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Bakker RA,
    2. Wieland K,
    3. Timmerman H, and
    4. Leurs R
    (2000) Constitutive activity of the histamine H(1) receptor reveals inverse agonism of histamine H(1) receptor antagonists. Eur J Pharmacol 387:R5–R7.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Black JW,
    2. Duncan WA,
    3. Durant CJ,
    4. Ganellin CR, and
    5. Parsons EM
    (1972) Definition and antagonism of histamine H 2 -receptors. Nature 236:385–390.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Bockaert J,
    2. Marin P,
    3. Dumuis A, and
    4. Fagni L
    (2003) The ‘magic tail’ of G protein-coupled receptors: an anchorage for functional protein networks. FEBS Lett 546:65–72.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Bonini JS,
    2. Da Silva WC,
    3. Da Silveira CKB,
    4. Köhler CA,
    5. Izquierdo I, and
    6. Cammarota M
    (2011) Histamine facilitates consolidation of fear extinction. Int J Neuropsychopharmacol 14:1209–1217.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Burde R,
    2. Buschauer A, and
    3. Seifert R
    (1990) Characterization of histamine H2-receptors in human neutrophils with a series of guanidine analogues of impromidine. Are cell type-specific H2-receptors involved in the regulation of NADPH oxidase? Naunyn Schmiedebergs Arch Pharmacol 341:455–461.
    OpenUrlPubMed
  15. ↵
    1. Burde R,
    2. Seifert R,
    3. Buschauer A, and
    4. Schultz G
    (1989) Histamine inhibits activation of human neutrophils and HL-60 leukemic cells via H2-receptors. Naunyn Schmiedebergs Arch Pharmacol 340:671–678.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Busse WW,
    2. Middleton E,
    3. Storms W,
    4. Dockhorn RJ,
    5. Chu TJ,
    6. Grossman J,
    7. Weiler JM,
    8. Bronsky EA,
    9. Mansfield LE,
    10. Bell TD,
    11. et al.
    (1996) Corticosteroid-sparing effect of azelastine in the management of bronchial asthma. Am J Respir Crit Care Med 153:122–127.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Buyse M,
    2. Michiels S,
    3. Squifflet P,
    4. Lucchesi KJ,
    5. Hellstrand K,
    6. Brune ML,
    7. Castaigne S, and
    8. Rowe JM
    (2011) Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission. Haematologica 96:1106–1112.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Colucci R,
    2. Fleming JV,
    3. Xavier R, and
    4. Wang TC
    (2001) L-histidine decarboxylase decreases its own transcription through downregulation of ERK activity. Am J Physiol Gastrointest Liver Physiol 281:G1081–G1091.
    OpenUrlAbstract/FREE Full Text
    1. de Almeida DO,
    2. Ferreira HS,
    3. Pereira LB, and
    4. Fregoneze JB
    (2015) Hypertensive response to stress: the role of histaminergic H1 and H2 receptors in the medial amygdala. Physiol Behav 144:95–102.
    OpenUrlCrossRef
  20. ↵
    1. Deva S and
    2. Jameson M
    (2012) Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer. Cochrane Database Syst Rev 8:CD007814.
    OpenUrlPubMed
  21. ↵
    1. Di Roberto RB,
    2. Chang B,
    3. Trusina A, and
    4. Peisajovich SG
    (2016) Evolution of a G protein-coupled receptor response by mutations in regulatory network interactions. Nat Commun 7:12344.
    OpenUrlCrossRef
  22. ↵
    1. Dong H,
    2. Zhang W,
    3. Zeng X,
    4. Hu G,
    5. Zhang H,
    6. He S, and
    7. Zhang S
    (2014) Histamine induces upregulated expression of histamine receptors and increases release of inflammatory mediators from microglia. Mol Neurobiol 49:1487–1500.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Eckel L,
    2. Gristwood RW,
    3. Nawrath H,
    4. Owen DA, and
    5. Satter P
    (1982) Inotropic and electrophysiological effects of histamine on human ventricular heart muscle. J Physiol 330:111–123.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Ezeamuzie CI and
    2. Philips E
    (2000) Histamine H(2) receptors mediate the inhibitory effect of histamine on human eosinophil degranulation. Br J Pharmacol 131:482–488.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Fernandez N,
    2. Gottardo FL,
    3. Alonso MN,
    4. Monczor F,
    5. Shayo C, and
    6. Davio C
    (2011) Roles of phosphorylation-dependent and -independent mechanisms in the regulation of histamine H2 receptor by G protein-coupled receptor kinase 2. J Biol Chem 286:28697–28706.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Fernandez N,
    2. Monczor F,
    3. Baldi A,
    4. Davio C, and
    5. Shayo C
    (2008) Histamine H2 receptor trafficking: role of arrestin, dynamin, and clathrin in histamine H2 receptor internalization. Mol Pharmacol 74:1109–1118.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Fernández N,
    2. Monczor F,
    3. Lemos B,
    4. Notcovich C,
    5. Baldi A,
    6. Davio C, and
    7. Shayo C
    (2002) Reduction of G protein-coupled receptor kinase 2 expression in U-937 cells attenuates H2 histamine receptor desensitization and induces cell maturation. Mol Pharmacol 62:1506–1514.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Fitzsimons CP,
    2. Monczor F,
    3. Fernández N,
    4. Shayo C, and
    5. Davio C
    (2004) Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein. J Biol Chem 279:34431–34439.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Galandrin S and
    2. Bouvier M
    (2006) Distinct signaling profiles of beta1 and beta2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy. Mol Pharmacol 70:1575–1584.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Galeotti N,
    2. Malmberg-Aiello P,
    3. Bartolini A,
    4. Schunack W, and
    5. Ghelardini C
    (2004) H1-receptor stimulation induces hyperalgesia through activation of the phospholipase C-PKC pathway. Neuropharmacology 47:295–303.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Gespach C and
    2. Abita JP
    (1982) Human polymorphonuclear neutrophils. Pharmacological characterization of histamine receptors mediating the elevation of cyclic AMP. Mol Pharmacol 21:78–85.
    OpenUrlAbstract
  32. ↵
    1. Glass JR,
    2. Sproule BA,
    3. Herrmann N, and
    4. Busto UE
    (2008) Effects of 2-week treatment with temazepam and diphenhydramine in elderly insomniacs: a randomized, placebo-controlled trial. J Clin Psychopharmacol 28:182–188.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Gutowski S,
    2. Smrcka A,
    3. Nowak L,
    4. Wu DG,
    5. Simon M, and
    6. Sternweis PC
    (1991) Antibodies to the alpha q subfamily of guanine nucleotide-binding regulatory protein alpha subunits attenuate activation of phosphatidylinositol 4,5-bisphosphate hydrolysis by hormones. J Biol Chem 266:20519–20524.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Haas HL and
    2. Panula P
    (2016) Histamine receptors. Neuropharmacology 106:1–2.
    OpenUrlCrossRef
  35. ↵
    1. Hattori Y
    (1999) Cardiac histamine receptors: their pharmacological consequences and signal transduction pathways. Methods Find Exp Clin Pharmacol 21:123–131.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Hellstrand K
    (2002) Histamine in cancer immunotherapy: a preclinical background. Semin Oncol 29 (Suppl 7):35–40.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Hershcovici T and
    2. Fass R
    (2011) Gastro-oesophageal reflux disease: beyond proton pump inhibitor therapy. Drugs 71:2381–2389.
    OpenUrlCrossRefPubMed
    1. Hirschfeld J,
    2. Buschauer A,
    3. Elz S,
    4. Schunack W,
    5. Ruat M,
    6. Traiffort E, and
    7. Scwartz JC
    (1992) Iodoaminopotentidine and related compounds: a new class of ligands with high affinity and selectivity for the histamine H2 receptor. J Med Chem 35:2231–2238.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Hishinuma S,
    2. Komazaki H,
    3. Fukui H, and
    4. Shoji M
    (2010) Ubiquitin/proteasome-dependent down-regulation following clathrin-mediated internalization of histamine H1-receptors in Chinese hamster ovary cells. J Neurochem 113:990–1001.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Huang R,
    2. Southall N,
    3. Wang Y,
    4. Yasgar A,
    5. Shinn P,
    6. Jadhav A,
    7. Nguyen DT, and
    8. Austin CP
    (2011) The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci Transl Med 3:80ps16.
    OpenUrlFREE Full Text
  41. ↵
    1. Iwakiri K,
    2. Kinoshita Y,
    3. Habu Y,
    4. Oshima T,
    5. Manabe N,
    6. Fujiwara Y,
    7. Nagahara A,
    8. Kawamura O,
    9. Iwakiri R,
    10. Ozawa S,
    11. et al.
    (2016) Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2015. J Gastroenterol 51:751–767.
    OpenUrlCrossRef
  42. ↵
    1. Iwata K,
    2. Luo J,
    3. Penn RB, and
    4. Benovic JL
    (2005) Bimodal regulation of the human H1 histamine receptor by G protein-coupled receptor kinase 2. J Biol Chem 280:2197–2204.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Jordan JD,
    2. Landau EM, and
    3. Iyengar R
    (2000) Signaling networks: the origins of cellular multitasking. Cell 103:193–200.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Jutel M,
    2. Akdis M, and
    3. Akdis CA
    (2009) Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy 39:1786–1800.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Kagawa Y,
    2. Izawa K,
    3. Yano H, and
    4. Kamei C
    (2010) Synergetic effects of prednisolone and olopatadine on atopic dermatitis model of hairless mice. Pharmacology 85:286–294.
    OpenUrlCrossRefPubMed
  46. ↵
    1. Kantor ED,
    2. Rehm CD,
    3. Haas JS,
    4. Chan AT, and
    5. Giovannucci EL
    (2015) Trends in prescription drug use among adults in the United States from 1999-2012. JAMA 314:1818–1831.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Kelley MT,
    2. Bürckstümmer T,
    3. Wenzel-Seifert K,
    4. Dove S,
    5. Buschauer A, and
    6. Seifert R
    (2001) Distinct interaction of human and guinea pig histamine H2-receptor with guanidine-type agonists. Mol Pharmacol 60:1210–1225.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Kenakin T
    (2004) Principles: receptor theory in pharmacology. Trends Pharmacol Sci 25:186–192.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Kenakin T and
    2. Miller LJ
    (2010) Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev 62:265–304.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Keogh R and
    2. Marley PD
    (1991) Regulation of cyclic AMP levels by calcium in bovine adrenal medullary cells. J Neurochem 57:1721–1728.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Kiefer TL,
    2. Lai L,
    3. Yuan L,
    4. Dong C,
    5. Burow ME, and
    6. Hill SM
    (2005) Differential regulation of estrogen receptor alpha, glucocorticoid receptor and retinoic acid receptor alpha transcriptional activity by melatonin is mediated via different G proteins. J Pineal Res 38:231–239.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Kingwell K
    (2015) Pioneering biased ligand offers efficacy with reduced on-target toxicity. Nat Rev Drug Discov 14:809–810.
    OpenUrlCrossRef
  53. ↵
    1. Kino T,
    2. Tiulpakov A,
    3. Ichijo T,
    4. Chheng L,
    5. Kozasa T, and
    6. Chrousos GP
    (2005) G protein beta interacts with the glucocorticoid receptor and suppresses its transcriptional activity in the nucleus. J Cell Biol 169:885–896.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    1. Kirch W,
    2. Halabi A, and
    3. Hinrichsen H
    (1992) Hemodynamic effects of quinidine and famotidine in patients with congestive heart failure. Clin Pharmacol Ther 51:325–333.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Koch M,
    2. Dezi A,
    3. Ferrario F, and
    4. Capurso I
    (1996) Prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal mucosal injury. A meta-analysis of randomized controlled clinical trials. Arch Intern Med 156:2321–2332.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Krystal AD,
    2. Lankford A,
    3. Durrence HH,
    4. Ludington E,
    5. Jochelson P,
    6. Rogowski R, and
    7. Roth T
    (2011) Efficacy and safety of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia. Sleep 34:1433–1442.
    OpenUrlPubMed
  57. ↵
    1. Krystal AD
    (2015) Current, emerging, and newly available insomnia medications. J Clin Psychiatry 76:e1045.
    OpenUrl
  58. ↵
    1. Laine L,
    2. Kivitz AJ,
    3. Bello AE,
    4. Grahn AY,
    5. Schiff MH, and
    6. Taha AS
    (2012) Double-blind randomized trials of single-tablet ibuprofen/high-dose famotidine vs. ibuprofen alone for reduction of gastric and duodenal ulcers. Am J Gastroenterol 107:379–386.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Leary PJ,
    2. Tedford RJ,
    3. Bluemke DA,
    4. Bristow MR,
    5. Heckbert SR,
    6. Kawut SM,
    7. Krieger EV,
    8. Lima JA,
    9. Masri CS,
    10. Ralph DD,
    11. et al.
    (2016) Histamine H2 receptor antagonists, left ventricular morphology, and heart failure risk: the MESA study. J Am Coll Cardiol 67:1544–1552.
    OpenUrlFREE Full Text
  60. ↵
    1. Leopoldt D,
    2. Harteneck C, and
    3. Nürnberg B
    (1997) G proteins endogenously expressed in Sf 9 cells: interactions with mammalian histamine receptors. Naunyn Schmiedebergs Arch Pharmacol 356:216–224.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Leurs R,
    2. Traiffort E,
    3. Arrang JM,
    4. Tardivel-Lacombe J,
    5. Ruat M, and
    6. Schwartz JC
    (1994) Guinea pig histamine H1 receptor. II. Stable expression in Chinese hamster ovary cells reveals the interaction with three major signal transduction pathways. J Neurochem 62:519–527.
    OpenUrlPubMed
  62. ↵
    1. Louis R,
    2. Schleich F, and
    3. Barnes PJ
    (2012) Corticosteroids: still at the frontline in asthma treatment? Clin Chest Med 33:531–541.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Lu NZ,
    2. Wardell SE,
    3. Burnstein KL,
    4. Defranco D,
    5. Fuller PJ,
    6. Giguere V,
    7. Hochberg RB,
    8. McKay L,
    9. Renoir JM,
    10. Weigel NL,
    11. et al.
    (2006) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev 58:782–797.
    OpenUrlFREE Full Text
  64. ↵
    1. Luo T,
    2. Chen B,
    3. Zhao Z,
    4. He N,
    5. Zeng Z,
    6. Wu B,
    7. Fukushima Y,
    8. Dai M,
    9. Huang Q,
    10. Xu D,
    11. et al.
    (2013) Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function. Basic Res Cardiol 108:342.
    OpenUrlCrossRefPubMed
  65. ↵
    1. Marley PD,
    2. Thomson KA,
    3. Jachno K, and
    4. Johnston MJ
    (1991) Histamine-induced increases in cyclic AMP levels in bovine adrenal medullary cells. Br J Pharmacol 104:839–846.
    OpenUrlCrossRefPubMed
  66. ↵
    1. Marshall BJ,
    2. Goodwin CS,
    3. Warren JR,
    4. Murray R,
    5. Blincow ED,
    6. Blackbourn SJ,
    7. Phillips M,
    8. Waters TE, and
    9. Sanderson CR
    (1988) Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 2:1437–1442.
    OpenUrlPubMed
  67. ↵
    1. Marshall BJ and
    2. Warren JR
    (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1:1311–1315.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Martner A,
    2. Thorén FB,
    3. Aurelius J,
    4. Söderholm J,
    5. Brune M, and
    6. Hellstrand K
    (2010) Immunotherapy with histamine dihydrochloride for the prevention of relapse in acute myeloid leukemia. Expert Rev Hematol 3:381–391.
    OpenUrlCrossRefPubMed
  69. ↵
    1. McHugh JM and
    2. McHugh WB
    (2000) Pain: neuroanatomy, chemical mediators, and clinical implications. AACN Clin Issues 11:168–178.
    OpenUrlCrossRefPubMed
  70. ↵
    1. Mettler SE,
    2. Ghayouri S,
    3. Christensen GP, and
    4. Forte JG
    (2007) Modulatory role of phosphoinositide 3-kinase in gastric acid secretion. Am J Physiol Gastrointest Liver Physiol 293:G532–G543.
    OpenUrlAbstract/FREE Full Text
  71. ↵
    1. Mobarakeh JI,
    2. Sakurada S,
    3. Katsuyama S,
    4. Kutsuwa M,
    5. Kuramasu A,
    6. Lin ZY,
    7. Watanabe T,
    8. Hashimoto Y,
    9. Watanabe T, and
    10. Yanai K
    (2000) Role of histamine H(1) receptor in pain perception: a study of the receptor gene knockout mice. Eur J Pharmacol 391:81–89.
    OpenUrlCrossRefPubMed
  72. ↵
    1. Monczor F,
    2. Copsel S,
    3. Fernandez N,
    4. Davio C, and
    5. Shayo C
    (2016) Histamine H2 receptor in blood cells: a suitable target for the treatment of acute myeloid leukemia. Handb Exp Pharmacol DOI: 10.1007/164_2016_8 [published ahead of print].
  73. ↵
    1. Monczor F,
    2. Fernandez N,
    3. Legnazzi BL,
    4. Riveiro ME,
    5. Baldi A,
    6. Shayo C, and
    7. Davio C
    (2003) Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model. Mol Pharmacol 64:512–520.
    OpenUrlAbstract/FREE Full Text
  74. ↵
    1. Monczor F,
    2. Legnazzi BL,
    3. Rivera E, and
    4. Davio C
    (1998) Tiotidine, a classical H2-antagonist, presents characteristics of an inverse agonist in U937 cell line. Inflamm Res 47 (Suppl 1):S42–S43.
    OpenUrlCrossRef
  75. ↵
    1. Moniri NH and
    2. Booth RG
    (2004) Functional heterogeneity of histamine H(1) receptors. Inflamm Res 53 (Suppl 1):S71–S72.
    OpenUrlCrossRefPubMed
  76. ↵
    1. Moniri NH and
    2. Booth RG
    (2006) Role of PKA and PKC in histamine H1 receptor-mediated activation of catecholamine neurotransmitter synthesis. Neurosci Lett 407:249–253.
    OpenUrlCrossRefPubMed
  77. ↵
    1. Moniri NH,
    2. Covington-Strachan D, and
    3. Booth RG
    (2004) Ligand-directed functional heterogeneity of histamine H1 receptors: novel dual-function ligands selectively activate and block H1-mediated phospholipase C and adenylyl cyclase signaling. J Pharmacol Exp Ther 311:274–281.
    OpenUrlAbstract/FREE Full Text
  78. ↵
    1. Morin CM,
    2. Koetter U,
    3. Bastien C,
    4. Ware JC, and
    5. Wooten V
    (2005) Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep 28:1465–1471.
    OpenUrlPubMed
  79. ↵
    1. Neubauer DN
    (2014) New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry 26:214–224.
    OpenUrlCrossRef
  80. ↵
    1. Nosengo N
    (2016) Can you teach old drugs new tricks? Nature 534:314–316.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Notcovich C,
    2. Diez F,
    3. Tubio MR,
    4. Baldi A,
    5. Kazanietz MG,
    6. Davio C, and
    7. Shayo C
    (2010) Histamine acting on H1 receptor promotes inhibition of proliferation via PLC, RAC, and JNK-dependent pathways. Exp Cell Res 316:401–411.
    OpenUrlCrossRefPubMed
  82. ↵
    1. Olbe L,
    2. Carlsson E, and
    3. Lindberg P
    (2003) A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat Rev Drug Discov 2:132–139.
    OpenUrlCrossRefPubMed
  83. ↵
    1. Ostrom NK
    (2014) The history and progression of treatments for allergic rhinitis. Allergy Asthma Proc 35 (Suppl 1):S3–S10.
    OpenUrlCrossRef
  84. ↵
    1. Pantziarka P,
    2. Bouche G,
    3. Meheus L,
    4. Sukhatme V, and
    5. Sukhatme VP
    (2014) Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. Ecancermedicalscience 8:485.
    OpenUrl
  85. ↵
    1. Panula P,
    2. Chazot PL,
    3. Cowart M,
    4. Gutzmer R,
    5. Leurs R,
    6. Liu WLS,
    7. Stark H,
    8. Thurmond RL, and
    9. Haas HL
    (2015) International Union of Basic and Clinical Pharmacology. XCVIII. Histamine receptors. Pharmacol Rev 67:601–655.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    1. Parsons ME and
    2. Ganellin CR
    (2006) Histamine and its receptors. Br J Pharmacol 147 (Suppl 1):S127–S135.
    OpenUrlCrossRefPubMed
  87. ↵
    1. Pincus SH,
    2. DiNapoli AM, and
    3. Schooley WR
    (1982) Superoxide production by eosinophils: activation by histamine. J Invest Dermatol 79:53–57.
    OpenUrlCrossRefPubMed
  88. ↵
    1. Pini A,
    2. Obara I,
    3. Battell E,
    4. Chazot PL, and
    5. Rosa AC
    (2016) Histamine in diabetes: is it time to reconsider? Pharmacol Res 111:316–324.
    OpenUrlCrossRef
  89. ↵
    1. Prast H and
    2. Philippu A
    (2001) Nitric oxide as modulator of neuronal function. Prog Neurobiol 64:51–68.
    OpenUrlCrossRefPubMed
  90. ↵
    1. Pupo AS,
    2. Duarte DA,
    3. Lima V,
    4. Teixeira LB,
    5. Parreiras-E-Silva LT, and
    6. Costa-Neto CM
    (2016) Recent updates on GPCR biased agonism. Pharmacol Res DOI: 10.1016/j.phrs.2016.01.031 [published ahead of print].
  91. ↵
    1. Rajagopal S,
    2. Rajagopal K, and
    3. Lefkowitz RJ
    (2010) Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 9:373–386.
    OpenUrlCrossRefPubMed
  92. ↵
    1. Reher TM,
    2. Brunskole I,
    3. Neumann D, and
    4. Seifert R
    (2012a) Evidence for ligand-specific conformations of the histamine H(2)-receptor in human eosinophils and neutrophils. Biochem Pharmacol 84:1174–1185.
    OpenUrlCrossRefPubMed
  93. ↵
    1. Reher TM,
    2. Neumann D,
    3. Buschauer A, and
    4. Seifert R
    (2012b) Incomplete activation of human eosinophils via the histamine H4-receptor: evidence for ligand-specific receptor conformations. Biochem Pharmacol 84:192–203.
    OpenUrlCrossRefPubMed
  94. ↵
    1. Richelson E
    (1978) Histamine H1 receptor-mediated guanosine 3′,5′-monophosphate formation by cultured mouse neuroblastoma cells. Science 201:69–71.
    OpenUrlAbstract/FREE Full Text
  95. ↵
    1. Rocha SM,
    2. Pires J,
    3. Esteves M,
    4. Graça B, and
    5. Bernardino L
    (2014) Histamine: a new immunomodulatory player in the neuron-glia crosstalk. Front Cell Neurosci 8:120.
    OpenUrl
  96. ↵
    1. Rocha SM,
    2. Saraiva T,
    3. Cristóvão AC,
    4. Ferreira R,
    5. Santos T,
    6. Esteves M,
    7. Saraiva C,
    8. Je G,
    9. Cortes L,
    10. Valero J,
    11. et al.
    (2016) Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation. J Neuroinflammation 13:137.
    OpenUrlCrossRef
  97. ↵
    1. Rostom A,
    2. Dube C,
    3. Wells G,
    4. Tugwell P,
    5. Welch V,
    6. Jolicoeur E, and
    7. McGowan J
    (2002) Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev (4):CD002296.
  98. ↵
    1. Rothenberg ME and
    2. Hogan SP
    (2006) The eosinophil. Annu Rev Immunol 24:147–174.
    OpenUrlCrossRefPubMed
    1. Sadek B and
    2. Stark H
    (2016) Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology 106:56–73.
    OpenUrlCrossRef
  100. ↵
    1. Sadik CD,
    2. Kim ND, and
    3. Luster AD
    (2011) Neutrophils cascading their way to inflammation. Trends Immunol 32:452–460.
    OpenUrlCrossRefPubMed
  101. ↵
    1. Sakurada S,
    2. Watanabe H,
    3. Mizoguchi H,
    4. Yonezawa A,
    5. Orito T,
    6. Katsuyama S,
    7. Kuramasu A,
    8. Sakurada C,
    9. Yanai K, and
    10. Sakurada T
    (2004) Involvement of the histaminergic system in the nociceptin-induced pain-related behaviors in the mouse spinal cord. Pain 112:171–182.
    OpenUrlCrossRefPubMed
  102. ↵
    1. Scharf M,
    2. Rogowski R,
    3. Hull S,
    4. Cohn M,
    5. Mayleben D,
    6. Feldman N,
    7. Ereshefsky L,
    8. Lankford A, and
    9. Roth T
    (2008) Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry 69:1557–1564.
    OpenUrlCrossRefPubMed
  103. ↵
    1. Schmidt P,
    2. Holsboer F, and
    3. Spengler D
    (2001) Beta(2)-adrenergic receptors potentiate glucocorticoid receptor transactivation via G protein beta gamma-subunits and the phosphoinositide 3-kinase pathway. Mol Endocrinol 15:553–564.
    OpenUrlCrossRefPubMed
  104. ↵
    1. Seifert R,
    2. Grünbaum L, and
    3. Schultz G
    (1994) Histamine H1-receptors in HL-60 monocytes are coupled to Gi-proteins and pertussis toxin-insensitive G-proteins and mediate activation of Ca2+ influx without concomitant Ca2+ mobilization from intracellular stores. Naunyn Schmiedebergs Arch Pharmacol 349:355–361.
    OpenUrlCrossRefPubMed
  105. ↵
    1. Shan L,
    2. Dauvilliers Y, and
    3. Siegel JM
    (2015) Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol 11:401–413.
    OpenUrlCrossRefPubMed
  106. ↵
    1. Shayo C,
    2. Fernandez N,
    3. Legnazzi BL,
    4. Monczor F,
    5. Mladovan A,
    6. Baldi A, and
    7. Davio C
    (2001) Histamine H2 receptor desensitization: involvement of a select array of G protein-coupled receptor kinases. Mol Pharmacol 60:1049–1056.
    OpenUrlAbstract/FREE Full Text
  107. ↵
    1. Shi GP,
    2. Bot I, and
    3. Kovanen PT
    (2015) Mast cells in human and experimental cardiometabolic diseases. Nat Rev Cardiol 12:643–658.
    OpenUrlCrossRefPubMed
  108. ↵
    1. Sigterman KE,
    2. van Pinxteren B,
    3. Bonis PA,
    4. Lau J, and
    5. Numans ME
    (2013) Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 5:CD002095.
    OpenUrlPubMed
  109. ↵
    1. Simons FE and
    2. Simons KJ
    (2011) Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol 128:1139–1150.e4.
    OpenUrlCrossRefPubMed
  110. ↵
    1. Smit MJ,
    2. Leurs R,
    3. Alewijnse AE,
    4. Blauw J,
    5. Van Nieuw Amerongen GP,
    6. Van De Vrede Y,
    7. Roovers E, and
    8. Timmerman H
    (1996) Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors. Proc Natl Acad Sci USA 93:6802–6807.
    OpenUrlAbstract/FREE Full Text
  111. ↵
    1. Smith AD,
    2. Gillen D,
    3. Cochran KM,
    4. El-Omar E, and
    5. McColl KE
    (1999) Dyspepsia on withdrawal of ranitidine in previously asymptomatic volunteers. Am J Gastroenterol 94:1209–1213.
    OpenUrlPubMed
  112. ↵
    1. Snider RM,
    2. McKinney M,
    3. Forray C, and
    4. Richelson E
    (1984) Neurotransmitter receptors mediate cyclic GMP formation by involvement of arachidonic acid and lipoxygenase. Proc Natl Acad Sci USA 81:3905–3909.
    OpenUrlAbstract/FREE Full Text
  113. ↵
    1. Soehnlein O,
    2. Lindbom L, and
    3. Weber C
    (2009) Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood 114:4613–4623.
    OpenUrlAbstract/FREE Full Text
  114. ↵
    1. Solelhac G and
    2. Charpin D
    (2014) Management of allergic rhinitis. F1000Prime Rep 6:94.
    OpenUrl
  115. ↵
    1. Stein T,
    2. Souza-Silva E,
    3. Mascarin L,
    4. Eto C,
    5. Fin FE, and
    6. Tonussi CR
    (2016) Histaminergic pharmacology modulates the analgesic and antiedematogenic effects of spinally injected morphine. Anesth Analg 123:238–243.
    OpenUrlCrossRef
  116. ↵
    1. Takahama H,
    2. Asanuma H,
    3. Sanada S,
    4. Fujita M,
    5. Sasaki H,
    6. Wakeno M,
    7. Kim J,
    8. Asakura M,
    9. Takashima S,
    10. Minamino T,
    11. et al.
    (2010) A histamine H₂ receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade. Basic Res Cardiol 105:787–794.
    OpenUrlCrossRefPubMed
  117. ↵
    1. Traiffort E,
    2. Ruat M,
    3. Arrang JM,
    4. Leurs R,
    5. Piomelli D, and
    6. Schwartz JC
    (1992) Expression of a cloned rat histamine H2 receptor mediating inhibition of arachidonate release and activation of cAMP accumulation. Proc Natl Acad Sci USA 89:2649–2653.
    OpenUrlAbstract/FREE Full Text
  118. ↵
    1. Tubio MR,
    2. Fernandez N,
    3. Fitzsimons CP,
    4. Copsel S,
    5. Santiago S,
    6. Shayo C,
    7. Davio C, and
    8. Monczor F
    (2010) Expression of a G protein-coupled receptor (GPCR) leads to attenuation of signaling by other GPCRs: experimental evidence for a spontaneous GPCR constitutive inactive form. J Biol Chem 285:14990–14998.
    OpenUrlAbstract/FREE Full Text
  119. ↵
    1. Violin JD,
    2. Crombie AL,
    3. Soergel DG, and
    4. Lark MW
    (2014) Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci 35:308–316.
    OpenUrlCrossRef
  120. ↵
    1. Wang YX and
    2. Kotlikoff MI
    (2000) Signalling pathway for histamine activation of non-selective cation channels in equine tracheal myocytes. J Physiol 523:131–138.
    OpenUrlCrossRefPubMed
  121. ↵
    1. Wei H,
    2. Ahn S,
    3. Shenoy SK,
    4. Karnik SS,
    5. Hunyady L,
    6. Luttrell LM, and
    7. Lefkowitz RJ
    (2003) Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci USA 100:10782–10787.
    OpenUrlAbstract/FREE Full Text
  122. ↵
    1. Weng G,
    2. Bhalla US, and
    3. Iyengar R
    (1999) Complexity in biological signaling systems. Science 284:92–96.
    OpenUrlAbstract/FREE Full Text
  123. ↵
    1. Wenzel-Seifert K,
    2. Kelley MT,
    3. Buschauer A, and
    4. Seifert R
    (2001) Similar apparent constitutive activity of human histamine H(2)-receptor fused to long and short splice variants of G(salpha). J Pharmacol Exp Ther 299:1013–1020.
    OpenUrlAbstract/FREE Full Text
  124. ↵
    1. Xu AJ,
    2. Kuramasu A,
    3. Maeda K,
    4. Kinoshita K,
    5. Takayanagi S,
    6. Fukushima Y,
    7. Watanabe T,
    8. Yanagisawa T,
    9. Sukegawa J, and
    10. Yanai K
    (2008) Agonist-induced internalization of histamine H2 receptor and activation of extracellular signal-regulated kinases are dynamin-dependent. J Neurochem 107:208–217.
    OpenUrlCrossRefPubMed
  125. ↵
    1. Zappia CD,
    2. Granja-Galeano G,
    3. Fernández N,
    4. Shayo C,
    5. Davio C,
    6. Fitzsimons CP, and
    7. Monczor F
    (2015) Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Sci Rep 5:17476.
    OpenUrlCrossRef
  126. ↵
    1. Zeng Z,
    2. Shen L,
    3. Li X,
    4. Luo T,
    5. Wei X,
    6. Zhang J,
    7. Cao S,
    8. Huang X,
    9. Fukushima Y,
    10. Bin J,
    11. et al.
    (2014) Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis. Clin Sci (Lond) 127:435–448.
    OpenUrlCrossRef
Back to top

In this issue

Download PDF
Article Alerts
Email Article
Citation Tools

Research ArticleMinireview—A Latin American Perspective On G Protein-Coupled Receptors

Histamine Receptor Pharmacology

Federico Monczor and Natalia Fernandez
Molecular Pharmacology November 1, 2016, 90 (5) 640-648; DOI: https://doi.org/10.1124/mol.116.105981
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo

Jump to section

Advertisement