Developmental activation of calmodulin-dependent facilitation of cerebellar P-type Ca2+ current

J Neurosci. 2005 Sep 7;25(36):8282-94. doi: 10.1523/JNEUROSCI.2253-05.2005.

Abstract

P-type (CaV2.1) Ca2+ channels are a central conduit of neuronal Ca2+ entry, so their Ca2+ feedback regulation promises widespread neurobiological impact. Heterologous expression of recombinant CaV2.1 channels demonstrates that the Ca2+ sensor calmodulin can trigger Ca2+-dependent facilitation (CDF) of channel opening. This facilitation occurs when local Ca2+ influx through individual channels selectively activates the C-terminal lobe of calmodulin. In neurons, however, such calmodulin-mediated processes have yet to be detected, and CDF of native P-type current has thus far appeared different, arguably triggered by other Ca2+ sensing molecules. Here, in cerebellar Purkinje somata abundant with prototypic P-type channels, we find that the C-terminal lobe of calmodulin does produce CDF, and such facilitation augments Ca2+ entry during stimulation by repetitive action-potential and complex-spike waveforms. Beyond recapitulating key features of recombinant channels, these neurons exhibit an additional modulatory dimension: developmental upregulation of CDF during postnatal week 2. This phenomenon reflects increasing somatic expression of CaV2.1 splice variants that manifest CDF and progressive dendritic targeting of variants lacking CDF. Calmodulin-triggered facilitation is thus fundamental to native CaV2.1 and rapidly enhanced during early development.

Publication types

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

MeSH terms

  • Animals
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, P-Type / drug effects
  • Calcium Channels, P-Type / physiology*
  • Calmodulin / pharmacology*
  • Cell Line
  • Cerebellum / physiology
  • Humans
  • Kidney
  • Nimodipine / pharmacology
  • Plasmids
  • Purkinje Cells / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Tetrodotoxin / pharmacology
  • Transfection

Substances

  • Calcium Channel Blockers
  • Calcium Channels, P-Type
  • Calmodulin
  • Tetrodotoxin
  • Nimodipine