Abstract
The kinetics of Ca2+ release from canine cerebellum and rabbit skeletal muscle microsomes, mediated by the inositol 1,4,5-trisphosphate (IP 3) receptor (IRC) and the ryanodine receptor (RyRC), respectively, were analyzed by a model, which considers that Ca 2+ release channels undergo spontaneous inactivation. We found that: (i) both the initial rate of release (v o) and the rate of inactivation (v 1) were saturable functions of the activating ligand concentration (C L); and (ii) the ratio of v i/v o, termed the relative tendency for inactivation, decreased with increasing C L. Equilibrium [ 3H]-IP 3 binding studies, on the other hand, revealed the presence of one single class of non-co-operative IP 3 sites in cerebellum membranes (K deq = 47 nM and Hill coefficient = 1.1). Based on the above v i−v o relationship and the IP 3-binding data, we propose that quantal Ca 2+ release through IRCs might be a result of spontaneous channel inactivation, whose rate is controlled by the ratio of IP 3-occupied/free monomers in the tetrameric release channel units. Furthermore, because of the kinetic similarities between the IRC- and RyRC-mediated Ca 2+ release processes, as well as between quantal Ca 2+ release and channel adaptation, the same mechanism is also proposed to apply to the RyRC-mediated Ca 2+ release as well as to constitute the basis of release channel adaptation.
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