TY - JOUR
T1 - 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
AU - Gaisano, Herbert Y.
AU - Miller, Laurence J.
AU - Foskett, J. Kevin
PY - 1994/7
Y1 - 1994/7
N2 - 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.
AB - 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.
KW - CCK
KW - Ca mobilization
KW - Enzyme secretion
KW - JMV 180
KW - OPE
KW - Pancreatic acinar cell
KW - Protein kinase C
KW - Receptor affinity state
UR - http://www.scopus.com/inward/record.url?scp=0028177923&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028177923&partnerID=8YFLogxK
U2 - 10.1007/BF00374261
DO - 10.1007/BF00374261
M3 - Article
C2 - 7971144
AN - SCOPUS:0028177923
SN - 0031-6768
VL - 427
SP - 455
EP - 462
JO - Pflügers Archiv European Journal of Physiology
JF - Pflügers Archiv European Journal of Physiology
IS - 5-6
ER -