Molecular Basis of Multiple Open States in Smooth Muscle Calcium Channels and Related Intracellular Signalling

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It is known that some smooth muscles possess both low- (LVA) and high voltage-activated (HVA) Ca^<2+> channel currents, and that the HVA current component is predominant in all smooth muscles. Previously, we have suggested that the conversion of the Ca^<2+> channel conformation from normal open (O1) to a second open state (O2) during large depoalrization is distinct from the long channel opening induced by Ca^<2+> channel agonists, and that these two mechanisms operate separately. As a result, a combination of DHP Ca^<2+> channel agonists and depolarization produces at least four open states in native smooth muscle Ca^<2+> channels.During the tenure of the present research project entitled 'Molecular Basis of Multiple Open States in Smooth Muscle Calcium Channels and Related Intracellular Signalling', we have first examined whether the multiple open state model can systematically account for the characteristic features of 'U-shaped inactivation' and 'slow deactivation' in CHO cells exp … More ressing only smooth muscle _1 subunit of L-type Ca^<2+> channel (Ca,1.2b), using patch clamp techniques. The experiments have revealed that smooth muscle _1 subunit alone can reproduce 'U-shaped inactivation' and 'slow deactivation' properties, and also interaction of highly positive conditioning steps and Ca^<2+> agonists. The results imply that intramolecular structural changes and/or interactions in _1 subunit protein play the central roles. Furthermore, we have reconstructed the slow deactivation and U-shaped inactivation properties seen in cloned smooth muscle Ca^<2+> channels using computer calculation with multiple open state models. Taken Together, it is concluded that that the conformation of _1 subunit of L-type Ca2+ channel can be converted from O1 to O2 state in a voltage-dependent manner. This conversion is not predicted from the gating model described by Hodgkin & Huxley. We would like to propose that some modification in this basic model is presumably necessary to describe gating kinetics under more general conditions. Less