Modulation of inactivation properties of CaV2.2 channels by 14-3-3 proteins

Neuron. 2006 Sep 21;51(6):755-71. doi: 10.1016/j.neuron.2006.08.014.

Abstract

Inactivation of presynaptic Ca(V)2.2 channels may play a role in regulating short-term synaptic plasticity. Here, we report a direct modulation of Ca(V)2.2 channel inactivation properties by 14-3-3, a family of signaling proteins involved in a wide range of biological processes. The structural elements critical for 14-3-3 binding and channel modulation lie in the carboxyl tail of the pore-forming alpha(1B) subunit, where we have identified two putative 14-3-3 interaction sites, including a phosphoserine-containing motif that directly binds to 14-3-3 and a second region near the EF hand and IQ domain. In transfected tsA 201 cells, 14-3-3 coexpression dramatically slows open-state inactivation and reduces cumulative inactivation of Ca(V)2.2 channels. In hippocampal neurons, interference with 14-3-3 binding accelerates Ca(V)2.2 channel inactivation and enhances short-term synaptic depression. These results demonstrate that 14-3-3 proteins are important regulators of Ca(V)2.2 channel activities and through this mechanism may contribute to their regulation of synaptic transmission and plasticity.

Publication types

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

MeSH terms

  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / metabolism
  • 14-3-3 Proteins / physiology*
  • Amino Acid Sequence
  • Animals
  • Binding Sites / genetics
  • Binding, Competitive
  • Blotting, Western
  • Brain / cytology
  • Brain / metabolism*
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism
  • Calcium Channels, N-Type / genetics
  • Calcium Channels, N-Type / metabolism*
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism
  • Cell Line
  • Cells, Cultured
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Humans
  • Neurons / cytology
  • Neurons / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Synaptic Transmission / physiology
  • Time Factors

Substances

  • 14-3-3 Proteins
  • Calcium Channels, L-Type
  • Calcium Channels, N-Type
  • Calcium Channels, T-Type
  • L-type calcium channel alpha(1C)
  • Protein Subunits
  • Recombinant Fusion Proteins
  • Glutathione Transferase