QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.070086v1 311/1/274    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moniri, N. H. Articles by Booth, R. G. Search for Related Content PubMed PubMed Citation Articles by Moniri, N. H. Articles by Booth, R. G.

CELLULAR AND MOLECULAR

Ligand-Directed Functional Heterogeneity of Histamine H₁ Receptors: Novel Dual-Function Ligands Selectively Activate and Block H₁-Mediated Phospholipase C and Adenylyl Cyclase Signaling

Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

The autacoid and neurotransmitter histamine activates the H₁ G protein-coupled receptor (GPCR) to stimulate predominantly phospholipase C (PLC)/inositol phosphate (IP) signaling and, to a lesser extent, adenylyl cyclase (AC)/cAMP signaling in a variety of mammalian cells and tissues, as well as H₁-transfected clonal cell lines. This study reports that two novel H₁ receptor ligands developed in our laboratory, (-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (trans-PAT) and (±)-cis-5-phenyl-7-dimethylamino-5,6,7,8-tetrahydro-9H-benzocycloheptane (cis-PAB), activate H₁ receptors to selectively stimulate AC/cAMP formation and PLC/IP formation, respectively, in Chinese hamster ovary cells transfected with guinea pig H₁ receptor cDNA. trans-PAT and cis-PAB also are shown to be functionally selective antagonists of H₁-linked PLC/IP and AC/cAMP signaling, respectively. Whereas cis-PAB H₁ receptor activity is shown to be typically competitive, trans-PAT displays a complex interaction with the H₁ receptor that is not competitive regarding antagonism of saturation binding by the standard H₁ antagonist radioligand [³H]mepyramine or H₁/PLC/IP functional activation by histamine. trans-PAT, however, does competitively block H₁/PLC/IP functional activation by cis-PAB. Molecular determinants for trans-PAT versus cis-PAB differential binding to H₁ receptors, which presumably leads to differential activation of AC/cAMP versus PLC/IP signaling, likely involves stereochemical factors as well as more subtle steric influences. Results suggest the trans-PAT and cis-PAB probes will be useful to study molecular mechanisms of ligand-directed GPCR multifunctional signaling. Moreover, because most untoward cardiovascular-, respiratory-, and gastrointestinal H₁ receptor-mediated effects proceed via the PLC/IP pathway, PAT-type agonists that selectively enhance H₁-mediated AC/cAMP signaling provide a mechanistic basis for exploiting H₁ receptor activation for drug design purposes.

Address correspondence to: Dr. Raymond G. Booth, Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. E-mail: rbooth{at}email.unc.edu

This article has been cited by other articles:

				S. Galandrin and M. Bouvier 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., November 1, 2006; 70(5): 1575 - 1584. [Abstract] [Full Text] [PDF]