(Hypertension. 1999;34:1152-1162.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Time-Dependent Effects of the Neuropeptide PACAP on Catecholamine Secretion
Stimulation and Desensitization
From the Department of Medicine and Center for Molecular Genetics, University of California, and V.A. San Diego Healthcare System, San Diego, Calif.
Correspondence to Laurent Taupenot, PhD, University of California, San Diego, Department of Medicine (9111H), 3350 La Jolla Village Dr, San Diego, CA 92161-9111H, USA. E-mail ltaupenot{at}ucsd.edu
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 IC50 doses of PACAP
for desensitization were 
18- to 32-fold lower than the
EC50 activating doses for secretion or transcription.
Desensitization of the initial secretion response was associated with
decreased Ca2+ influx through L-type voltage-operated
Ca2+ channels. Acute exposure to PACAP also triggered
long-lasting (up to 3 hours), extracellular Ca2+-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-ß
inhibitor (U-73122) blocked this extended secretory
response, which was dependent on low-magnitude Ca2+ influx
resistant to several L-, N-, P/Q-, or T-type Ca2+
channel antagonists, but sensitive to Zn2+,
Ni2+, Cd2+, or to the store-operated
Ca2+ channel blocker SKF96365. A less than additive effect
of the sarco-endoplasmic reticulum Ca2+-ATPase
inhibitor thapsigargin plus PACAP on this sustained
secretion also supported a contribution of store-operated
Ca2+ 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 Ca2+ channel, extended secretion may
involve a store-operated Ca2+ channel that is
activated through a Gq/11/phospholipase
C-ß/phosphoinositide signaling pathway.
Key Words: PC12 • chromaffin • chromogranin • peptides • catecholamines • desensitization
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