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

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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.

TABLE 1

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

Signaling	H₁R		H₂R
Signaling	Pathway, Ligand, or Receptor	Reference	Pathway, Ligand, or Receptor	Reference
Main signaling pathway involved	Gq/11/PLC/Ca²⁺/PKC; Rac, RhoA	Gutowski et al. (1991), Notcovich et al. (2010)	Gs/AC/PKA	Panula et al. (2015)
Other signaling pathways regulated	Gi/0; PLA2; AC/cAMP; NF-κB	Snider et al. (1984), Leurs et al. (1994), Seifert et al. (1994), Bakker et al. (2001), Prast and Philippu (2001)	Gq/11; PLA2; ERK1/2; PI3K	Leopoldt et al. (1997), Mettler et al. (2007), Bonini et al. (2011), Luo et al. (2013), Alonso et al. (2016)
Classic reference ligand	Mepyramine	Sadek and Stark (2016)	Iodoaminopotentidine	Hirschfeld et al. (1992)
Biased ligands	(−) trans-PAT; (±) cis-PAB	Moniri et al. (2004)	Famotidine; cimetidine; tiotidine; ranitidine	Alonso et al. (2014, 2015)
Crosstalk with other receptors	ATP receptor; GR	Fitzsimons et al. (2004), Zappia et al. (2015)	β-adrenergic receptor; calcitonin receptor; PGE2 receptor	Monczor et al. (2003), Tubio et al. (2010)

NF-κB, nuclear factor-κB; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PKC, protein kinase C; PLA, phospholipase A.

TABLE 2

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

H₁R				H₂R
Molecular Mechanism of Action	Therapeutic Use	Pharmacological Effect	Reference	Molecular Mechanism of Action	Therapeutic Use	Pharmacological Effect	Reference
	Current	Antiallergic	Bakker et al. (2001), Panula et al. (2015)	Gs/AC/cAMP inhibition	Current	Gastric acid secretion regulation	Panula et al. (2015)
Gq/11 activity blockade; NF-κB inhibition	Repositioning	Analgesia; neurodegenerative disorders; sleep disorders; stress induced hypertension	Krystal et al. (2011), de Almeida et al. (2015), Shan et al. (2015), Apolloni et al. (2016), Rocha et al. (2016), Stein et al. (2016)	Gs/AC/cAMP inhibition	Repositioning	Chronic heart failure; diabetes; colorectal cancer	Pantziarka et al. (2014), Leary et al. (2016), Pini et al. (2016)
Biased agonism; GR crosstalk	Nontraditional	Neuroprotection; anti-inflammatory potentiation	Moniri et al. (2004), Zappia et al. (2015)	Biased agonism	Nontraditional	Gastric acid secretion rebound; AML treatment	Reher et al. (2012a,b), Alonso et al. (2014, 2015)