Feedback inhibition of Ca2+ release by Ca2+ is the underlying mechanism of agonist-evoked intracellular Ca2+ oscillations in pancreatic acinar cells

B. X. Zhang, S. Muallem

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Oscillations of free intracellular Ca2+ concentration ([Ca2+](i)) are known to occur in many cell types during physiological cell signaling. To identify the basis for the oscillations, we measured both [Ca2+](i) and extracellular Ca2+ concentration ([Ca2+](o)) to follow the fate of Ca2+ during stimulation of [Ca2+](i) oscillations in pancreatic acinar cells. [Ca2+](i) oscillations were initiated by either t-butyloxycarbonyl- Tyr(SO3)-Nle-Gly-Tyr-Nle-Asp-2-phenylethyl ester (CCK-J), which mobilized Ca2+ from the inositol 1,4,5-trisphosphate (IP3)-insensitive pool, or low concentration of cholecystokinin octapeptide (CCK-OP), which mobilized Ca2+ from the IP3-sensitive internal pool. Little Ca2+ efflux occurred during the oscillations triggered by CCK-J or CCK-OP in spite of a large average increase in [Ca2+](i). When internal store Ca2+ pumps were inhibited with thapsigargin (Tg) during [Ca2+](i) oscillations, a rapid Ca2+ efflux occurred similar to that measured in intensely stimulated, nonoscillatory cells. Tg also stimulated 45Ca efflux from internal pools of cells stimulated with CCK-J or a low concentration of CCK-OP. Hence, a large fraction of the Ca2+ released during each spike is reincorporated by the internal store Ca2+ pumps. Surprisingly, when the increase in [Ca2+](i) during stimulation of oscillations was prevented by loading the cells with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, a persistent activation of Ca2+ release and Ca2+ efflux occurred. This was reflected as a persistent increase in [Ca2+](o) in cells suspended at low [Ca2+](o) or persistent efflux of 45Ca from internal stores of cells maintained at high [Ca2+](o). Since agonist-stimulated Ca2+ release evidently remains activated when [Ca2+](i) is highly buffered, the primary mechanism determining Ca2+ oscillations must include an inhibition of Ca2+ release by [Ca2+](i). Loading the cells with 1,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid had no apparent effect on the levels or kinetics of IP3 formation in agonist-stimulated cells. This suggests that [Ca2+](i) regulated the oscillation by inhibition of Ca2+ release independent of its possible effects on cellular levels of IP3.

Original languageEnglish (US)
Pages (from-to)24387-24393
Number of pages7
JournalJournal of Biological Chemistry
Issue number34
StatePublished - 1992

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Feedback inhibition of Ca2+ release by Ca2+ is the underlying mechanism of agonist-evoked intracellular Ca2+ oscillations in pancreatic acinar cells'. Together they form a unique fingerprint.

Cite this