Synaptotagmin-7 Enhances Facilitation of Ca_v2.1 Calcium Channels

Voltage-gated calcium channel Ca_v2.1 undergoes Ca²⁺-dependent facilitation and inactivation, which are important in short-term synaptic plasticity. In presynaptic terminals, Ca_v2.1 forms large protein complexes that include synaptotagmins. Synaptotagmin-7 (Syt-7) is essential to mediate short-term synaptic plasticity in many synapses. Here, based on evidence that Ca_v2.1 and Syt-7 are both required for short-term synaptic facilitation, we investigated the direct interaction of Syt-7 with Ca_v2.1 and probed its regulation of Ca_v2.1 function. We found that Syt-7 binds specifically to the α_1A subunit of Ca_v2.1 through interaction with the synaptic-protein interaction (synprint) site. Surprisingly, this interaction enhances facilitation in paired-pulse protocols and accelerates the onset of facilitation. Syt-7α induces a depolarizing shift in the voltage dependence of activation of Ca_v2.1 and slows Ca²⁺-dependent inactivation, whereas Syt-7β and Syt-7γ have smaller effects. Our results identify an unexpected, isoform-specific interaction between Ca_v2.1 and Syt-7 through the synprint site, which enhances Ca_v2.1 facilitation and modulates its inactivation.