Interplay of voltage and Ca-dependent inactivation of L-type Ca current

Inactivation of L-type Ca channels (LTCC) is regulated by both Ca and voltage-dependent processes (CDI and VDI). To differentiate VDI and CDI, several experimental and theoretical studies have considered the inactivation of Ba current through LTCC (IBa) as a measure of VDI. However, there is evidence that Ba can weakly mimic Ca, such that IBa inactivation is still a mixture of CDI and VDI. To avoid this complication, some have used the monovalent cation current through LTCC (INS), which can be measured when divalent cation concentrations are very low. Notably, INS inactivation rate does not depend on current amplitude, and hence may reflect purely VDI. However, based on analysis of existent and new data, and modeling, we find that INS can inactivate more rapidly and completely than IBa, especially at physiological temperature. Thus VDI that occurs during IBa (or ICa) must differ intrinsically from VDI during INS. To account for this, we have extended a previously published LTCC mathematical model of VDI and CDI into an excitation-contraction coupling model, and assessed whether and how experimental IBa inactivation results (traditionally used in VDI experiments and models) could be recapitulated by modifying CDI to account for Ba-dependent inactivation. Thus, the view of a slow and incomplete INS inactivation should be revised, and INS inactivation is a poor measure of VDI during ICa or IBa. This complicates VDI analysis experimentally, but raises intriguing new questions about how the molecular mechanisms of VDI differ for divalent and monovalent currents through LTCCs.