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Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214
Address all correspondence and requests for reprints to: Dr. S. Laychock, 102 Farber Hall, Department of Pharmacology and Toxicology, State University of New York at Buffalo, School of Medicine, Buffalo, New York 14214[hyphen3000. E-mail: laychock{at}acsu.buffalo.edu
Inositol 1,4,5-trisphosphate receptor (IP3R) protein levels in isolated
rat pancreatic islets were investigated in response to carbachol (CCh)
and sulfated cholecystokinin 26–33 amide stimulation. Within 2 h,
CCh reduced IP3R-I protein levels by 22% and IP3R-II and -III levels
to 65% or more below basal. Sulfated cholecystokinin 26–33 amide
decreased the levels of IP3R-I, -II, and -III by 34%, 60%, and 66%
below basal, respectively. The effect of CCh was concentration- and
time-dependent, with a persistent decline in IP3R levels for up to
6 h after the onset of stimulation. CCh-pretreated islets also
showed an inhibition of glucose-stimulated insulin secretion.
Proteasome inhibition completely blocked the down-regulatory effects of
CCh on IP3Rs and significantly increased the insulin secretory response
to glucose stimulation in the presence of CCh. Islet stimulation by
glucose, 
-ketoisocaproic acid, and tolbutamide completely protected
IP3Rs against the down-regulatory effects of CCh. 2-deoxyglucose and
3-O-methyl glucose failed to affect CCh-induced IP3R down-regulation.
The protective effects of glucose on IP3R down-regulation were
completely inhibited by the Ca2+ channel-blocking agent
nimodipine. Intracellular Ca2+
([Ca2+]i) levels in Fura-2 (fluorescent
Ca2+ indicator)-loaded islets, in the absence of
extracellular Ca2+, increased in response to glucose
stimulation; but in islets pretreated with CCh, glucose did not
increase [Ca2+]i above basal levels. However,
in islets pretreated with CCh and the proteasomal inhibitor MG-132
(carbobenzoxyl-leucinyl-leucinyl-leucinyl-H), the
glucose-stimulated increase in [Ca2+]i was
significantly higher than the change observed for glucose-stimulated
[Ca2+]i in the absence of MG-132. The results
suggest that muscarinic receptor stimulation modulates IP3R protein
levels in islets through a proteasomal activation pathway, and that
down-regulation of IP3Rs has a profound effect on Ca2+
mobilization in islets that may relate to insulin secretory
responsiveness.
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