SUPPRESSION OF CA2-CELLS BY LOW-LEVEL PROTEIN-KINASE-C ACTIVATION WITHOUT TRANSITION OF THE CCK RECEPTOR FROM A HIGH-AFFINITY TO LOW-AFFINITY STATE( OSCILLATIONS INDUCED BY CHOLECYSTOKININ (CCK) AND ITS ANALOGOPE IN RAT PANCREATIC ACINAR)

Citation
Hy. Gaisano et al., SUPPRESSION OF CA2-CELLS BY LOW-LEVEL PROTEIN-KINASE-C ACTIVATION WITHOUT TRANSITION OF THE CCK RECEPTOR FROM A HIGH-AFFINITY TO LOW-AFFINITY STATE( OSCILLATIONS INDUCED BY CHOLECYSTOKININ (CCK) AND ITS ANALOGOPE IN RAT PANCREATIC ACINAR), Pflugers Archiv, 427(5-6), 1994, pp. 455-462
Citations number
33
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Physiology
Journal title
ISSN journal
0031-6768
Volume
427
Issue
5-6
Year of publication
1994
Pages
455 - 462
Database
ISI
SICI code
0031-6768(1994)427:5-6<455:SOCBLP>2.0.ZU;2-0
Abstract
Cholecystokinin (CCK) analogs, JMV-180 and OPE, release Ca2+ from intr acellular stores and induce oscillations in the concentration of cytos olic Ca2+ ([Ca2+](i)), but do not generate a detectable rise in inosit ol 1,4,5-trisphosphate (InsP(3)) levels. In contrast, high concentrati ons of CCK elevate InsP(3), as well [Ca2+](i), to a peak which decreas es to near basal levels without oscillations. The mechanisms which und erlie inhibition of [Ca2+](i) oscillations observed with high CCK conc entrations are unclear, but are believed to involve a low-affinity CCK receptor state. Alternately, CCK analogs may be weak partial agonists of the phospholipase C pathway, whereas native CCK, as a full agonist of this pathway, stimulates low levels of protein kinase C (PKC) acti vity. Preincubation of acini with 1 nM 12 O-tetradecanoyl-phorbol 13-a cetate (TPA) for 15 min at 37 degrees C did not affect OPE binding to acini, but abolished OPE-induced (at 1 mu M) [Ca2+](i) oscillations wi thout affecting the initial [Ca2+](i) spike. These transformed OPE-ind uced [Ca2+](i) responses mimicked those induced by supramaximal CCK oc tapeptide (CCK-8) concentrations. Inhibition of [Ca2+](i) oscillations by 1 nM TPA was reversed by the PKC inhibitor staurosporine (0.2 mu M ). After [Ca2+](i) oscillations were induced with OPE or low concentra tions of CCK-8 (20 pM), 1 nM TPA caused a gradual slowing of oscillati on frequency over 15-20 min without affecting [Ca2+](i) spike amplitud e. In contrast, 1 CIM TPA inhibited OPE binding and caused a more gene ralized inhibition of OPE- and CCK-evoked Ca2+ signals. These data sug gest that inhibitory effects of low-level PKC activation on agonist-ev oked Ca2+ signalling are distinct from the effects of high-level PKC a ctivation by 1 mu M TPA, and do not require the transition of the CCK receptor from a high-affinity to a low-affinity state.