Time-Dependent Effects of the Neuropeptide PACAP on Catecholamine Secretion
Open Access
- 1 November 1999
- journal article
- other
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 34 (5), 1152-1162
- https://doi.org/10.1161/01.hyp.34.5.1152
Abstract
Abstract —Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a potent endogenous secretagogue for chromaffin cells. We previously reported that PACAP coupled to the PAC1 receptor to evoke dihydropyridine-sensitive early (15 to 20 minutes) catecholamine secretion and cAMP response element binding protein–mediated trans- activation of the secretory protein chromogranin A promoter in PC12 pheochromocytoma cells. In this report, we studied whether the secretory and transcriptional responses elicited by PACAP were subject to desensitization. We found that PACAP evoked distinct immediate (initial, 0 to 20 minutes) and long-lasting (20 to 180 minutes) effects on catecholamine secretion. Initial secretory and chromogranin A trans -activation responses induced by PACAP were desensitized in a dose-dependent fashion after preexposure of cells to PACAP, and the IC 50 doses of PACAP for desensitization were ≈18- to ≈32-fold lower than the EC 50 activating doses for secretion or transcription. Desensitization of the initial secretion response was associated with decreased Ca 2+ influx through L-type voltage-operated Ca 2+ channels. Acute exposure to PACAP also triggered long-lasting (up to 3 hours), extracellular Ca 2+ -dependent, pertussis toxin–insensitive catecholamine secretion; indeed, even after short-term (20 minutes) exposure to PACAP and removal of the secretagogue, PC12 cells continued to secrete norepinephrine up to 76.9±0.22% of cellular norepinephrine content after 3 hours. A phospholipase C-β inhibitor (U-73122) blocked this extended secretory response, which was dependent on low-magnitude Ca 2+ influx resistant to several L-, N-, P/Q-, or T-type Ca 2+ channel antagonists, but sensitive to Zn 2+ , Ni 2+ , Cd 2+ , or to the store-operated Ca 2+ channel blocker SKF96365 . A less than additive effect of the sarco-endoplasmic reticulum Ca 2+ -ATPase inhibitor thapsigargin plus PACAP on this sustained secretion also supported a contribution of store-operated Ca 2+ entry to the sustained secretory response. We propose that PACAP-evoked secretion and transcription are subject to homologous desensitization in PC12 cells; however, PACAP also induces long-lasting secretion, even under dose and time circumstances in which acute, dihydropyridine-sensitive secretion has been desensitized. Although initial secretion is mediated by an L-type voltage-operated Ca 2+ channel, extended secretion may involve a store-operated Ca 2+ channel that is activated through a G q/11 /phospholipase C-β/phosphoinositide signaling pathway.Keywords
This publication has 46 references indexed in Scilit:
- Functional Coupling of Secretion and Capacitative Calcium Entry in PC12 CellsBiochemical and Biophysical Research Communications, 1998
- Stimulus-transcription Coupling in Pheochromocytoma CellsPublished by Elsevier BV ,1996
- Activation of tyrosine hydroxylase by pituitary adenylate cyclase-activating polypeptide (PACAP-27) in bovine adrenal chromaffin cellsJournal of the Autonomic Nervous System, 1996
- PACAP and VIP Stimulate Ca2+ Oscillations in Rat Gonadotrophs through the PACAP/VIP Type 1 Receptor (PVR1) Linked to a Pertussis Toxin‐Insensitive G‐Protein and the Activation of Phospholipase C‐βJournal of Neuroendocrinology, 1996
- Proteins that interact with the pore-forming subunits of voltage-gated ion channelsCurrent Opinion in Neurobiology, 1995
- G-protein regulation of ion channelsCurrent Opinion in Neurobiology, 1995
- Cell type-specific gene expression in the neuroendocrine system. A neuroendocrine-specific regulatory element in the promoter of chromogranin A, a ubiquitous secretory granule core protein.JCI Insight, 1994
- Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neuronsNeuropharmacology, 1993
- Multiple types of neuronal calcium channels and their selective modulationTrends in Neurosciences, 1988
- Desensitization to Nicotinic Cholinergic Agonists and K+, Agents That Stimulate Catecholamine Secretion, in Isolated Adrenal Chromaffin CellsJournal of Neurochemistry, 1984