Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies

Channels (Austin). Mar-Apr 2009;3(2):110-21. doi: 10.4161/chan.3.2.7932. Epub 2009 Mar 23.

Abstract

Alternative splicing is known to generate multiple functionally distinct calcium channel variants that exhibit unique spatial and temporal expression patterns. In humans, naturally occurring mutations in genes encoding calcium channel pore forming alpha(1)-subunits are associated with several severe hereditary disorders although it remains to be described whether there exists any relationship between the physiological effects of these mutations and calcium channel splice variation. In the present study, we systematically compare the biophysical effects of three type-1 familial hemiplegic migraine (FHM-1) mutations in two predominant splice variants of the neuronal Ca(V)2.1 P/Q-type channel. All three FHM-1 mutations cause a greater hyperpolarizing shift in voltage-dependent properties when expressed in the short carboxyl terminus variant (Ca(V)2.1 Delta47) compared to the long variant (Ca(V)2.1 +47). Furthermore, the FHM-1 mutations also exhibit differential splice variant-specific effects on recovery from inactivation and accumulation of inactivation during tonic and burst firing. Our findings provide important insight concerning the role of calcium channel alternatively spliced variants and the molecular pathophysiology of FHM-1 and potentially of other calcium channelopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Alternative Splicing / physiology*
  • Calcium Channels, N-Type / genetics*
  • Cerebral Cortex / chemistry
  • Electrophysiology
  • Humans
  • Membrane Potentials
  • Migraine with Aura / genetics*
  • Migraine with Aura / physiopathology
  • Mutation

Substances

  • Calcium Channels, N-Type
  • voltage-dependent calcium channel (P-Q type)