Facilitation versus depression in cultured hippocampal neurons determined by targeting of Ca²⁺ channel Ca_vβ₄ versus Ca_vβ₂ subunits to synaptic terminals

Ca²⁺ channel β subunits determine the transport and physiological properties of high voltage–activated Ca²⁺ channel complexes. Our analysis of the distribution of the Ca_vβ subunit family members in hippocampal neurons correlates their synaptic distribution with their involvement in transmitter release. We find that exogenously expressed Ca_vβ_4b and Ca_vβ_2a subunits distribute in clusters and localize to synapses, whereas Ca_vβ_1b and Ca_vβ₃ are homogenously distributed. According to their localization, Ca_vβ_2a and Ca_vβ_4b subunits modulate the synaptic plasticity of autaptic hippocampal neurons (i.e., Ca_vβ_2a induces depression, whereas Ca_vβ_4b induces paired-pulse facilitation [PPF] followed by synaptic depression during longer stimuli trains). The induction of PPF by Ca_vβ_4b correlates with a reduction in the release probability and cooperativity of the transmitter release. These results suggest that Ca_vβ subunits determine the gating properties of the presynaptic Ca²⁺ channels within the presynaptic terminal in a subunit-specific manner and may be involved in organization of the Ca²⁺ channel relative to the release machinery.