title: Pituitary adenylate cyclase-activating polypeptides directly stimulate sympathetic neuron neuropeptide Y release through PAC(1) receptor isoform activation of specific intracellular signaling pathways.
abstract: Pituitary adenylate cyclase-activating polypeptides (PACAP) have potent regulatory and neurotrophic activities on superior cervical ganglion (SCG) sympathetic neurons with pharmacological profiles consistent for the PACAP-selective PAC(1) receptor. Multiple PAC(1) receptor isoforms are suggested to determine differential peptide potency and receptor coupling to multiple intracellular signaling pathways. The current studies examined rat SCG PAC(1) receptor splice variant expression and coupling to intracellular signaling pathways mediating PACAP-stimulated peptide release. PAC(1) receptor mRNA was localized in over 90% of SCG neurons, which correlated with the cells expressing receptor protein. The neurons expressed the PAC(1)(short)HOP1 receptor but not VIP/PACAP-nonselective VPAC(1) receptors; low VPAC(2) receptor mRNA levels were restricted to ganglionic nonneuronal cells. PACAP27 and PACAP38 potently and efficaciously stimulated both cAMP and inositol phosphate production; inhibition of phospholipase C augmented PACAP-stimulated cAMP production, but inhibition of adenylyl cyclase did not alter stimulated inositol phosphate production. Phospholipase C inhibition blunted neuron peptide release, suggesting that the phosphatidylinositol pathway was a prominent component of the secretory response. These studies demonstrate preferential sympathetic neuron expression of PACAP-selective receptor variants contributing to regulation of autonomic function.
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Braas
authors.forename: V
authors.initials: V
authors.lastname: May
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017398:Alternative Splicing; D000818:Animals; D000831:Animals, Newborn; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D014644:Genetic Variation; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009478:Neuropeptide Y / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D017433:Protein Structure, Secondary; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D018005:Receptors, Vasoactive Intestinal Peptide / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000502:physiology*; D014158:Transcription, Genetic; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: C495403:Adcyap1 protein, rat; D004791:Enzyme Inhibitors; D004963:Estrenes; D007295:Inositol Phosphates; D009478:Neuropeptide Y; D009479:Neuropeptides; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020033:Protein Isoforms; D011760:Pyrrolidinones; D012333:RNA, Messenger; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone; D018005:Receptors, Vasoactive Intestinal Peptide; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C017759:9-(tetrahydro-2-furyl)-adenine; D000242:Cyclic AMP; D010738:Type C Phospholipases; D000225:Adenine