Molecular Determinants of CaV2.1 Channel Regulation by Calcium-binding Protein-1

Presynaptic CaV2.1 channels, which conduct P/Q-type Ca2+ currents, initiate synaptic transmission at most synapses in the central nervous system. Regulation of CaV2.1 channels by CaM contributes significantly to short term facilitation and rapid depression of synaptic transmission. Short term synaptic plasticity is diverse in form and function at different synapses, yet CaM is ubiquitously expressed. Differential regulation of CaV2.1 channels by CaM-like Ca2+ sensor (CaS) proteins differentially affects short term synaptic facilitation and rapid synaptic depression in transfected sympathetic neuron synapses. Here, we define the molecular determinants for differential regulation of CaV2.1 channels by the CaS protein calcium-binding protein-1 (CaBP1) by analysis of chimeras in which the unique structural domains of CaBP1 are inserted into CaM. Our results show that the N-terminal domain, including its myristoylation site, and the second EF-hand, which is inactive in Ca2+ binding, are the key molecular determinants of differential regulation of CaV2.1 channels by CaBP1. These findings give insight into the molecular code by which CaS proteins differentially regulate CaV2.1 channel function and provide diversity of form and function of short term synaptic plasticity. Background: Regulation of calcium channels by calcium-sensor proteins mediates short term synaptic plasticity. Results: Calcium-binding protein-1 (CaBP1) inhibits calcium channels through its N terminus and second EF-hand, which is inactive in calcium binding. Conclusion: Specific domains of CaBP1 are responsible for differential regulation, including an EF-hand inactive in calcium binding. Significance: These results reveal the molecular code used by calcium-sensor proteins to differentially regulate short term synaptic plasticity.