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.
Highlights
The cloning of cDNAs for three putative seven-transmembrane G-protein-coupled receptors for VIP and Pituitary adenylate cyclase-activating polypeptides (PACAP) demonstrated receptor subtype diversity and functional heterogeneity [17,18,19,20,21,22,23,24,25]
PC12 cells (Fig. 1F), which express PACAP-selective receptor mRNA and respond potently to PACAP, but not VIP [11], stained, whereas no staining was observed in AtT-20/D16v cells, which are regulated by both PACAP and VIP but express VPAC2 receptor transcripts [35]
The present studies demonstrate that superior cervical ganglion (SCG) postganglionic neurons express predominantly the PAC1(short)HOP1 receptor splice variant coupled to both adenylyl cyclase and phospholipase C
Summary
The current studies examined rat SCG PAC1 receptor splice variant expression and coupling to intracellular signaling pathways mediating PACAP-stimulated peptide release. 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. Cell-specific expression of PAC1 receptor splice variants determines differential peptide potency and distinct patterns of adenylyl cyclase and phospholipase C stimulation by PACAP38 and PACAP27 [23]. To further evaluate the mechanisms mediating sympathetic neuron responses to PACAP, the present studies investigated SCG neuron expression of specific PAC1 receptor molecular forms and determined whether PACAP-stimulated receptor activation of specific second messenger pathways modulates peptide secretion.
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