Role of PKA and PKC in histamine H1 receptor-mediated activation of catecholamine neurotransmitter synthesis.
Activation of the histamine H1 receptor stimulates tyrosine hydroxylase (TH) to increase catecholamine neurotransmitter synthesis in mammalian brain and adrenal tissues. Histamine non-selectively activates both H1-linked phospholipase (PL) C/inositol phosphates (IP)/diacylglycerol (DAG) signaling and adenylyl cyclase (AC)/adenosine 3',5'-cyclic monophosphate (cAMP) signaling, confounding determination of signaling events involved in H(1)-mediated TH activation. This research uses two new functionally-selective H1 agonists, cis-PAB and trans-PAT, that selectively activate H1/PLC/IP/DAG and H1/AC/cAMP signaling, respectively, to characterize H(1)-mediated activation of TH in rat striatum and bovine adrenal chromaffin (BAC) cells. Histamine, cis-PAB, and trans-PAT produced a two-fold maximal TH activation by an H1 receptor mechanism in rat striatum and BAC cells. Histamine is more potent and efficacious in BAC cells (EC50 approximately 0.2 microM, Emax approximately 200% basal) versus rat striatum (EC50 approximately 0.4 microM; Emax approximately 150%). Cis-PAB and trans-PAT are more potent in rat striatum (EC50 approximately 0.1 microM for both agonists) versus BAC cells (EC50 approximately 1.0 microM for both), with similar efficacy in both preparations (Emax approximately 160% for both agonists). Signaling studies in BAC cells revealed that protein kinase (PK) A but not PKC is involved in H1 -mediated TH activation by trans-PAT and histamine, while, both PKA and PKC are involved for cis-PAB. Results for cis-PAB suggest H1/PLC/IP/DAG/PKC signaling activates PKA, downstream of cAMP formation, indicating apparent direct activation of PKA by PKC.
Moniri
Nader H
NH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC 25799-7360, USA.
Booth
Raymond G
RG
D000262:Adenylyl Cyclases / Q000502:physiology; D000313:Adrenal Medulla / Q000166:cytology; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002395:Catecholamines / Q000096:biosynthesis*; D002417:Cattle; D019439:Chromaffin Cells / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004075:Diglycerides / Q000502:physiology; D004123:Dimethylamines / Q000494:pharmacology; D004789:Enzyme Activation; D017442:Histamine Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000502:physiology; D008297:Male; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000502:physiology*; D015398:Signal Transduction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D010738:Type C Phospholipases / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C514930:5-phenyl-7-dimethylamino-5,6,7,8-tetrahydro-9H-benzocycloheptane; D001643:Bridged Bicyclo Compounds; D002395:Catecholamines; D004075:Diglycerides; D004123:Dimethylamines; D017442:Histamine Agonists; D007295:Inositol Phosphates; D011969:Receptors, Histamine H1; D013764:Tetrahydronaphthalenes; C084981:1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases