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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
Federico Monczor
Instituto de Investigaciones Farmacológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires, Argentina
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Natalia Fernandez
Instituto de Investigaciones Farmacológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires, Argentina
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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.

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    TABLE 1

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

    SignalingH1RH2R
    Pathway, Ligand, or ReceptorReferencePathway, Ligand, or ReceptorReference
    Main signaling pathway involvedGq/11/PLC/Ca2+/PKC; Rac, RhoAGutowski et al. (1991), Notcovich et al. (2010)Gs/AC/PKAPanula et al. (2015)
    Other signaling pathways regulatedGi/0; PLA2; AC/cAMP; NF-κBSnider et al. (1984), Leurs et al. (1994), Seifert et al. (1994), Bakker et al. (2001), Prast and Philippu (2001) Gq/11; PLA2; ERK1/2; PI3KLeopoldt et al. (1997), Mettler et al. (2007), Bonini et al. (2011), Luo et al. (2013), Alonso et al. (2016)
    Classic reference ligandMepyramineSadek and Stark (2016)IodoaminopotentidineHirschfeld et al. (1992)
    Biased ligands(−) trans-PAT; (±) cis-PABMoniri et al. (2004)Famotidine; cimetidine; tiotidine; ranitidineAlonso et al. (2014, 2015)
    Crosstalk with other receptorsATP receptor; GRFitzsimons et al. (2004), Zappia et al. (2015)β-adrenergic receptor; calcitonin receptor; PGE2 receptorMonczor 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.

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    TABLE 2

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

    H1RH2R
    Molecular Mechanism of ActionTherapeutic UsePharmacological EffectReferenceMolecular Mechanism of ActionTherapeutic UsePharmacological EffectReference
    CurrentAntiallergicBakker et al. (2001), Panula et al. (2015) Gs/AC/cAMP inhibitionCurrentGastric acid secretion regulationPanula et al. (2015)
    Gq/11 activity blockade; NF-κB inhibitionRepositioningAnalgesia; neurodegenerative disorders; sleep disorders; stress induced hypertensionKrystal et al. (2011), de Almeida et al. (2015), Shan et al. (2015), Apolloni et al. (2016), Rocha et al. (2016), Stein et al. (2016)RepositioningChronic heart failure; diabetes; colorectal cancerPantziarka et al. (2014), Leary et al. (2016), Pini et al. (2016)
    Biased agonism; GR crosstalkNontraditionalNeuroprotection; anti-inflammatory potentiationMoniri et al. (2004), Zappia et al. (2015)Biased agonismNontraditionalGastric acid secretion rebound; AML treatmentReher et al. (2012a,b), Alonso et al. (2014, 2015)
    • NF-κB, nuclear factor-κB.

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Molecular Pharmacology: 90 (5)
Molecular Pharmacology
Vol. 90, Issue 5
1 Nov 2016
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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

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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
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  • Article
    • Visual Overview
    • Abstract
    • Introduction
    • H1R and H2R Signaling
    • Biased Signaling at H1 and H2 Histamine Receptors
    • Histaminergic Regulation of the Signaling of Other Receptors
    • Pharmacology of H1 and H2 Histamine Receptors: From Classic Uses to Repurposing and Novel Indications
    • Final Considerations
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  • Histamine H3 Receptor
  • GPCR-Biased Signaling
  • Gβγ Pathways in Oncogenic GPCR Signaling
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