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

Abstract

Activation of cells by hormones, growth factors or neurotransmitters leads to an increased production of inositol trisphosphate (InsP₃) and, after activation of the InsP₃ receptor (InsP₃R), 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 InsP₃ 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 InsP₃-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 InsP₃- induced Ca²⁺ release include the presence of InsP₃Rs with varying sensitivities for InsP₃, heterogeneous InsP₃R distribution, intrinsic inactivation of the InsP₃Rs, and regulation of the InsP₃Rs 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 InsP₃R 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.