Mechanism of Ca(2+)-sensitive inactivation of L-type Ca2+ channels.
Many high threshold, voltage-gated Ca2+ channels, including the dihydropyridine-sensitive class (L-type), inactivate in response not only to voltage, but also to entry of Ca2+. Despite the physiological importance of this Ca(2+)-sensitive inactivation, its molecular mechanism is understood only in broad outline. We now demonstrate that Ca(2+)-dependent inactivation transpires by a Ca(2+)-induced shift of channel gating to a low open probability mode, distinguished by a more than 100-fold reduction of entry rate to the open state. A gating mechanism that explains this shift quantitatively and enables successful separation of Ca(2+)- and voltage-sensitive forms of inactivation is deduced and tested. Finally, both calmodulin activation and channel (de)phosphorylation are excluded as significant signaling events underlying Ca(2+)-induced mode shifts, leaving direct binding of Ca2+ to the channel as a likely chemical initiation event for inactivation.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
J P
JP
Imredy
D T
DT
Yue
D000818:Animals; D001464:Barium / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D015640:Ion Channel Gating; D008433:Mathematics; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D011336:Probability; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors
D015220:Calcium Channels; D004095:Dihydropyridines; D001464:Barium; C038806:1,4-dihydropyridine; D002118:Calcium