The Role of CaV2.1 Channel Facilitation in Synaptic Facilitation

Summary Activation of Ca V 2.1 voltage-gated calcium channels is facilitated by preceding calcium entry. Such self-modulatory facilitation is thought to contribute to synaptic facilitation. Using knockin mice with mutated Ca V 2.1 channels that do not facilitate (Ca IM-AA mice), we surprisingly found that, under conditions of physiological calcium and near-physiological temperatures, synaptic facilitation at hippocampal CA3 to CA1 synapses was not attenuated in Ca IM-AA mice and facilitation was paradoxically more prominent at two cerebellar synapses. Enhanced facilitation at these synapses is consistent with a decrease in initial calcium entry, suggested by an action-potential-evoked Ca V 2.1 current reduction in Purkinje cells from Ca IM-AA mice. In wild-type mice, Ca V 2.1 facilitation during high-frequency action potential trains was very small. Thus, for the synapses studied, facilitation of calcium entry through Ca V 2.1 channels makes surprisingly little contribution to synaptic facilitation under physiological conditions. Instead, Ca V 2.1 facilitation offsets Ca V 2.1 inactivation to produce remarkably stable calcium influx during high-frequency activation.