Ca2+ oscillations in hepatocytes do not require the modulation of InsP3 3-kinase activity by Ca2+

Abstract

Receptor-mediated production of inositol 1,4,5-trisphosphate (InsP3) initiates Ca2+ release and is responsible for cytosolic Ca2+ oscillations. InsP3 oscillations have also been observed in some cells. One of the enzymes controlling InsP3 catabolism, the InsP3 3-kinase, is stimulated by Ca2+; this regulation is presumably part of the reason for InsP3 oscillations that have been observed in some cells. Here, we investigate the possible role of Ca2+-activated InsP3 catabolism on the characteristics of the InsP3-induced Ca2+ oscillations. Numerical simulations show that if it is assumed that the Ca2+-independent InsP3 catabolism is predominant, Ca2+ oscillations remain qualitatively unchanged although the relative amplitude of the oscillations in InsP3 concentrations becomes minimal. We tested this prediction in hepatocytes by masking the Ca2+-dependent InsP3 catabolism by 3-kinase through the injection of massive amounts of InsP3 5-phosphatase, which is not stimulated by Ca2+. We find that in such injected hepatocytes, Ca2+ oscillations generated by modest agonist levels are suppressed, presumably because of the decreased dose in InsP3, but that at higher doses of agonist, oscillations reappear, with characteristics similar to those of untreated cells at low agonist doses. Altogether, these results suggest that oscillations in InsP3 concentration due to Ca2+-stimulated InsP3 catabolism do not play a major role for the oscillations in Ca2+ concentration. © 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.