Suppression of Ca2+ oscillations induced by cholecystokinin (CCK) and its analog OPE in rat pancreatic acinar cells by low-level protein kinase C activation without transition of the CCK receptor from a high- to low-affinity state

Herbert Y. Gaisano, Laurence J. Miller, J. Kevin Foskett

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Cholecystokinin (CCK) analogs, JMV-180 and OPE, release Ca2+ from intracellular stores and induce oscillations in the concentration of cytosolic Ca2+ ([Ca2+]i), but do not generate a detectable rise in inositol 1,4,5-trisphosphate (Ins P3) levels. In contrast, high concentrations of CCK elevate Ins P3, as well [Ca2+]i, to a peak which decreases to near basal levels without oscillations. The mechanisms which underlie inhibition of [Ca2+]i oscillations observed with high CCK concentrations 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) activity. Preincubation of acini with 1 nM 12 O-tetradecanoyl-phorbol 13-acetate (TPA) for 15 min at 37°C did not affect OPE binding to acini, but abolished OPE-induced (at 1 μM) [Ca2+]i oscillations without affecting the initial [Ca2+]i spike. These transformed OPE-induced [Ca2+]i responses mimicked those induced by supramaximal CCK octapeptide (CCK-8) concentrations. Inhibition of [Ca2+]i oscillations by 1 nM TPA was reversed by the PKC inhibitor staurosporine (0.2 μM). After [Ca2+]i oscillations were induced with OPE or low concentrations of CCK-8 (20 pM), 1 nM TPA caused a gradual slowing of oscillation frequency over 15-20 min without affecting [Ca2+]i spike amplitude. In contrast, 1 μM TPA inhibited OPE binding and caused a more generalized inhibition of OPE- and CCK-evoked Ca2+ signals. These data suggest that inhibitory effects of low-level PKC activation on agonist-evoked Ca2+ signalling are distinct from the effects of high-level PKC activation by 1 μM TPA, and do not require the transition of the CCK receptor from a high-affinity to a low-affinity state.

Original languageEnglish (US)
Pages (from-to)455-462
Number of pages8
JournalPflügers Archiv European Journal of Physiology
Volume427
Issue number5-6
DOIs
StatePublished - Jul 1 1994

Keywords

  • CCK
  • Ca mobilization
  • Enzyme secretion
  • JMV 180
  • OPE
  • Pancreatic acinar cell
  • Protein kinase C
  • Receptor affinity state

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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