Mechanisms responsible for quantal Ca2+ release from inositol trisphosphate-sensitive calcium stores

Activation of cells by hormones, growth factors or neurotransmitters leads to an increased production of inositol trisphosphate (InsP(3)) and, after activation of the InsP(3) receptor (InsP(3)R), to Ca2+ release from intracellular Ca2+ stores. The release of intracellular Ca2+ is characterised by a graded response when submaximal doses of agonists are used. The basic phenomenon, called ''quantal Ca2+ release'', is that even the maintained presence of a submaximal dose of agonist or of InsP(3) for long time periods (up to 20 min) provokes only a partial release of Ca2+. This partial, or quantal, release phenomenon is due to the fact that the initially very rapid InsP(3)-induced Ca2+ release eventually develops into a much slower release phase. Physiologically, quantal release allows the Ca2+ stores to function as increment detectors and to induce local Ca2+ responses. The basic mechanism for quantal release of Ca2+ is presently not known. Possible mechanisms to explain the quantal behaviour of InsP(3)-induced Ca2+ release include the presence of InsP(3)-Rs with varying sensitivities for InsP(3), heterogeneous InsP(3)R distribution, intrinsic inactivation of the InsP(3)Rs, and regulation of the InsP(3)Rs by Ca2+ store content. This article reviews critically the evidence for the various mechanisms and evaluates their functional importance. A Ca2+-mediated conformational change of the InsP(3)R is most likely the key feature of the mechanism for quantal Ca2+ release, but the exact mode of operation remains unclear. It should also be pointed out that in intact cells more than one mechanism can be involved.