Fine-tuning Synaptic Plasticity by Modulation of Presynaptic Calcium(V)2.1 Channels with Calcium(II) Sensor Proteins

Short-term plasticity of synaptic transmission is recognized as an important component of information processing in neuronal networks. Repetitive firing in neurons either leads to an increase, or to a decrease in synaptic transmission, processes referred to as facilitation and depression. This short-term plasticity behavior of synaptic transmission is specifically regulated at each given synaptic connection. P/Q-type and N-type Ca 2+ currents through Cav2.1 and Cav2.2 channels, respectively, are responsible for the Ca2+ entry that initiates neurotransmitter release at most conventional synapses. However, it remains not well understood to what extent regulation of Cav2.1 channels play a role in short-term plasticity. Recent work has shown Ca2+-dependent regulation of Cav2.1 channels to be mediated by calmodulin (CaM) and neuronal Ca sensors (CaS), which include calcium binding protein 1 (CaBP1) and visinin-like protein 2 (VILIP-2). Mutations of the CaS binding sites in the carboxyl terminal of Cav2.1 affect short-term synaptic plasticity. Although it is clear that CaS-dependent regulation of Cav2.1 channels induces synaptic plasticity, it remains unknown which CaS proteins are responsible for these changes. Candidate proteins include, CaM, CaBP1, and VILIP-2, which show differential modulation of Cav2.1 channels in heterologous expression systems; yet, their role in synaptic transmission has not been studied. Here, we show that activity-dependent modulation of presynaptic Ca V2.1 channels by CaBP1 and VILIP-2 has opposing effects on short-term synaptic plasticity in superior cervical ganglion (SCG) neurons. Expression of CaBP1, which blocks Ca2+-dependent facilitation of P/Q-type Ca2+ current, markedly reduced facilitation of synaptic transmission. VILIP-2, which blocks Ca2+-dependent inactivation of P/Q-type Ca2+ current, reduced synaptic depression and increased facilitation under conditions of high release probability. These results demonstrate that activity-dependent regulation of presynaptic CaV2.1 channels by differentially expressed CaS proteins can fine-tune synaptic responses to trains of action potentials and thereby contribute to the diversity of short-term synaptic plasticity.