Mechanism of Ca(2+)-sensitive Inactivation of L-type Ca2+ Channels

Neuron. 1994 Jun;12(6):1301-18. doi: 10.1016/0896-6273(94)90446-4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Barium / metabolism
  • Barium / pharmacology
  • Calcium / metabolism*
  • Calcium / pharmacology*
  • Calcium Channels / drug effects
  • Calcium Channels / physiology*
  • Cells, Cultured
  • Dihydropyridines / pharmacology
  • Heart / physiology*
  • Ion Channel Gating
  • Mathematics
  • Membrane Potentials / drug effects
  • Models, Biological
  • Probability
  • Rats
  • Signal Transduction
  • Time Factors

Substances

  • Calcium Channels
  • Dihydropyridines
  • Barium
  • 1,4-dihydropyridine
  • Calcium