The Role Of Ca(V)2.1 Channel Facilitation In Synaptic Facilitation

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 calciumand 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.