title: Ligand-directed functional heterogeneity of histamine H1 receptors: novel dual-function ligands selectively activate and block H1-mediated phospholipase C and adenylyl cyclase signaling.
abstract: The autacoid and neurotransmitter histamine activates the H(1) 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 H(1)-transfected clonal cell lines. This study reports that two novel H(1) 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 H(1) receptors to selectively stimulate AC/cAMP formation and PLC/IP formation, respectively, in Chinese hamster ovary cells transfected with guinea pig H(1) receptor cDNA. trans-PAT and cis-PAB also are shown to be functionally selective antagonists of H(1)-linked PLC/IP and AC/cAMP signaling, respectively. Whereas cis-PAB H(1) receptor activity is shown to be typically competitive, trans-PAT displays a complex interaction with the H(1) receptor that is not competitive regarding antagonism of saturation binding by the standard H(1) antagonist radioligand [(3)H]mepyramine or H(1)/PLC/IP functional activation by histamine. trans-PAT, however, does competitively block H(1)/PLC/IP functional activation by cis-PAB. Molecular determinants for trans-PAT versus cis-PAB differential binding to H(1) 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 H(1) receptor-mediated effects proceed via the PLC/IP pathway, PAT-type agonists that selectively enhance H(1)-mediated AC/cAMP signaling provide a mechanistic basis for exploiting H(1) receptor activation for drug design purposes.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
authors.forename: Nader H
authors.initials: NH
authors.lastname: Moniri
authors.forename: Dawn
authors.initials: D
authors.lastname: Covington-Strachan
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
mesh_terms: D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D011738:Pyrilamine / Q000494:pharmacology; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology*
chemical_list: D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D000242:Cyclic AMP; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases; D011738:Pyrilamine