Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces short-term synaptic facilitation

Mol Cell Neurosci. 2014 Nov:63:124-31. doi: 10.1016/j.mcn.2014.11.001.


Facilitation and inactivation of P/Q-type Ca2+ currents mediated by Ca2+/calmodulin binding to Ca(V)2.1 channels contribute to facilitation and rapid depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin from its binding site and differentially modulate P/Q-type Ca2 + currents, resulting in diverse patterns of short-term synaptic plasticity. Neuronal calcium sensor-1 (NCS-1, frequenin) has been shown to enhance synaptic facilitation, but the underlying mechanism is unclear. We report here that NCS-1 directly interacts with IQ-like motif and calmodulin-binding domain in the C-terminal domain of Ca(V)2.1 channel. NCS-1 reduces Ca2 +-dependent inactivation of P/Q-type Ca2+ current through interaction with the IQ-like motif and calmodulin-binding domain without affecting peak current or activation kinetics. Expression of NCS-1 in presynaptic superior cervical ganglion neurons has no effect on synaptic transmission, eliminating effects of this calcium sensor protein on endogenous N-type Ca2+ currents and the endogenous neurotransmitter release machinery. However, in superior cervical ganglion neurons expressing wild-type Ca(V)2.1 channels, co-expression of NCS-1 induces facilitation of synaptic transmission in response to paired pulses and trains of depolarizing stimuli, and this effect is lost in Ca(V)2.1 channels with mutations in the IQ-like motif and calmodulin-binding domain. These results reveal that NCS-1 directly modulates Ca(V)2.1 channels to induce short-term synaptic facilitation and further demonstrate that CaS proteins are crucial in fine-tuning short-term synaptic plasticity.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Calcium Channels, N-Type / chemistry
  • Calcium Channels, N-Type / metabolism*
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Mice
  • Neuronal Calcium-Sensor Proteins / genetics
  • Neuronal Calcium-Sensor Proteins / metabolism*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Protein Binding
  • Rats
  • Superior Cervical Ganglion / cytology
  • Superior Cervical Ganglion / metabolism
  • Superior Cervical Ganglion / physiology
  • Synapses / metabolism*
  • Synapses / physiology
  • Synaptic Transmission*


  • Calcium Channels, N-Type
  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • frequenin calcium sensor proteins
  • voltage-dependent calcium channel (P-Q type)