Molecular determinants of inactivation in voltage-gated Ca2+ channels

J Physiol. 2000 Oct 15;528 Pt 2(Pt 2):237-49. doi: 10.1111/j.1469-7793.2000.t01-1-00237.x.


Evolution has created a large family of different classes of voltage-gated Ca2+ channels and a variety of additional splice variants with different inactivation properties. Inactivation controls the amount of Ca2+ entry during an action potential and is, therefore, believed to play an important role in tissue-specific Ca2+ signalling. Furthermore, mutations in a neuronal Ca2+ channel (Ca(v)2.1) that are associated with the aetiology of neurological disorders such as familial hemiplegic migraine and ataxia cause significant changes in the process of channel inactivation. Ca2+ channels of a given subtype may inactivate by three different conformational changes: a fast and a slow voltage-dependent inactivation process and in some channel types by an additional Ca2+-dependent inactivation mechanism. Inactivation kinetics of Ca2+ channels are determined by the intrinsic properties of their pore-forming alpha1-subunits and by interactions with other channel subunits. This review focuses on structural determinants of Ca2+ channel inactivation in different parts of Ca2+ channel alpha1-subunits, including pore-forming transmembrane segments and loops, intracellular domain linkers and the carboxyl terminus. Inactivation is also affected by the interaction of the alpha1-subunits with auxiliary beta-subunits and intracellular regulator proteins. The evidence shows that pore-forming S6 segments and conformational changes in extra- (pore loop) and intracellular linkers connected to pore-forming segments may play a principal role in the modulation of Ca2+ channel inactivation. Structural concepts of Ca2+ channel inactivation are discussed.

Publication types

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

MeSH terms

  • Action Potentials
  • Alternative Splicing
  • Animals
  • Ataxia / genetics
  • Ataxia / metabolism
  • Binding Sites
  • Calcium Channels / chemistry
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling
  • GTP-Binding Proteins / metabolism
  • Humans
  • Kinetics
  • Membrane Proteins / metabolism
  • Migraine Disorders / genetics
  • Migraine Disorders / metabolism
  • Models, Molecular
  • Mutation
  • Protein Conformation
  • Protein Subunits
  • Qa-SNARE Proteins
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism


  • Calcium Channels
  • Membrane Proteins
  • Protein Subunits
  • Qa-SNARE Proteins
  • Recombinant Fusion Proteins
  • GTP-Binding Proteins