Ryanodine receptor adaptation and Ca2+-induced Ca2+ release-dependent Ca2+ oscillations

A simplified mechanism that mimics ''adaptation'' of the ryanodine receptor (RyR) has been developed and its significance for Ca2+-induced Ca2+ release and Ca2+ oscillations investigated. For parameters that reproduce experimental data for the RyR from cardiac cells, adaptation of the RyR in combination with sarco/endoplasmic reticulum Ca2+ ATPase Ca2+ pumps in the internal stores can give rise to either low [Ca-i(2+)] steady states or Ca2+ oscillations coexisting with unphysiologically high [Ca-i(2+)] steady states. In this closed-cell-type model rapid, adaptation-dependent Ca2+ oscillations occur only in limited ranges of parameters. In the presence of Ca2+ influx and efflux from outside the cell (open-cell model) Ca2+ oscillations occur for a wide range of physiological parameter values and have a period that is determined by the rate of Ca2+ refilling of the stores. Although the rate of adaptation of the RyR has a role in determining the shape and the period of the Ca2+ spike, it is not essential for their existence. This is in marked contrast with what is observed for the inositol 1,4,5-trisphosphate receptor for which the biphasic activation and inhibition of its activity by Ca2+ are sufficient to produce oscillations. Results for this model are compared with those based on Ca2+-induced Ca2+ release alone in the bullfrog sympathetic neuron. This kinetic model should be suitable for analyzing phenomena associated with ''Ca2+ sparks,'' including their merger into Ca2+ waves in cardiac myocytes.