KINETIC BASIS OF QUANTAL CALCIUM-RELEASE FROM INTRACELLULAR CALCIUM STOVES

The kinetics of Ca2+ release from canine cerebellum and rabbit skeleta l muscle microsomes, mediated by the inositol 1,4,5-trisphosphate (IP3 ) receptor (IRC) and the ryanodine receptor (RyRC), respectively, were analyzed by a model, which considers that Ca2+ release channels under go spontaneous inactivation. We found that: (i) both the initial rate of release (v(o)) and the rate of inactivation (v(i)) were saturable f unctions of the activating ligand concentration (C-L); and (ii) the ra tio of v(i)/v(o), termed the relative tendency for inactivation, decre ased with increasing C-L. Equilibrium [H-3]-IP3 binding studies, on th e other hand, revealed the presence of one single class of non-co-oper ative IP3 sites in cerebellum membranes (K-deq = 47 nM and Hill coeffi cient = 1.1). Based on the above v(i)-v(o) relationship and the IP3-bi nding data, we propose that quantal Ca2+ release through IRCs might be a result of spontaneous channel inactivation, whose rate is controlle d by the ratio of IP3-occupied/free monomers in the tetrameric release channel units. Furthermore, because of the kinetic similarities betwe en the IRC-and RyRC-mediated Ca2+ release processes, as well as betwee n quantal Ca2+ release and channel adaptation, the same mechanism is a lso proposed to apply to the RyRC-mediated Ca2+ release as well as to constitute the basis of release channel adaptation.