Kinetic model of the inositol trisphosphate receptor that shows both steady-state and quantal patterns of Ca2+ release from intracellular stores.

Abstract

The release of Ca(2+) from intracellular stores via InsP(3) receptors shows anomalous kinetics. Successive additions of low concentrations of InsP(3) cause successive rapid transients of Ca(2+) release. These quantal responses have been ascribed to all-or-none release from stores with differing sensitivities to InsP(3) or, alternatively, to a steady-state mechanism where complex kinetic properties of the InsP(3) receptor allow partial emptying of all the stores. We present here an adaptive model of the InsP(3) receptor that can show either pattern, depending on the imposed experimental conditions. The model proposes two interconvertible conformational states of the receptor: one state binds InsP(3) rapidly, but with low affinity, whereas the other state binds slowly, but with high affinity. The model shows repetitive increments of Ca(2+) release in the absence of a Ca(2+) gradient, but more pronounced incremental behaviour when released Ca(2+) builds up at the mouth of the channel. The sensitivity to Ins P (3) is critically dependent on the density of InsP(3) receptors, so that different stores can respond to different concentration ranges of Ins P (3). Since the model generates very high Hill coefficients (h approximately 7), it allows all-or-none release of Ca(2+) from stores of differing receptor density, but questions the validity of the use of h values as a guide to the number of InsP(3) molecules needed to open the channel. The model presents a mechanism for terminating Ca(2+) release in the presence of positive feedback from released Ca(2+), thereby providing an explanation of why elementary Ca(2+) signals ('blips' and 'puffs') do not inevitably turn into regenerative waves.