The release of Ca2+ from intracellular stores via InsP3 receptors shows anomalous kinetics. Successive additions of low concentrations of InsP3 cause successive rapid transients of Ca2+ release. These quantal responses have been ascribed to all-or-none release from stores with differing sensitivities to InsP3 or, alternatively, to a steady-state mechanism where complex kinetic properties of the InsP3 receptor allow partial emptying of all the stores. We present here an adaptive model of the InsP3 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 InsP3 rapidly, but with low affinity, whereas the other state binds slowly, but with high affinity. The model shows repetitive increments of Ca2+ release in the absence of a Ca2+ gradient, but more pronounced incremental behaviour when released Ca2+ builds up at the mouth of the channel. The sensitivity to InsP3 is critically dependent on the density of InsP3 receptors, so that different stores can respond to different concentration ranges of InsP3. Since the model generates very high Hill coefficients (h7), it allows all-or-none release of Ca2+ from stores of differing receptor density, but questions the validity of the use of h values as a guide to the number of InsP3 molecules needed to open the channel. The model presents a mechanism for terminating Ca2+ release in the presence of positive feedback from released Ca2+, thereby providing an explanation of why elementary Ca2+ signals ('blips’ and ‘puffs') do not inevitably turn into regenerative waves.

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