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"Calcium Channel Regulation, Synaptic Plasticity, and Spatial Learning" William Catterall

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William Catterall, University of Washington, Seattle USA

The voltage-gated calcium channel Cav2.1 is responsible for calcium entry that triggers fast neurotransmission at most synapses in the brain. This channel forms a large signaling complex in the presynaptic membrane, including G proteins, SNARE proteins, protein kinases, and calmodulin-like calcium sensor proteins. Interaction with SNARE proteins enhances the efficiency of neurotransmitter release. Interaction with G proteins, protein kinases, and calcium sensor proteins regulates calcium channel function. Single long depolarizations or long trains of brief depolarizations induce calcium-dependent facilitation of the calcium current followed by calcium-dependent inactivation. This biphasic regulation results from calcium binding to high affinity EF-hands 3 and 4 of calmodulin during brief stimuli, followed by further calcium binding to low affinity EF-hands 1 and 2 during prolonged stimulation. Transfection of Cav2.1 channels into cultured sympathetic neurons induces facilitation and rapid depression of neurotransmission, like a central synapse, and both facilitation and rapid depression depend on regulation of the transfected Cav2.1 channels by calcium sensor proteins. To test the significance of this form of synaptic regulation in vivo, we inserted the IM-AA mutation in the calcium sensor protein binding site in Cav2.1 channels in mice. These IM-AA mice have major impairments of synaptic regulation at the neuromuscular junction and in hippocampal synapses. At CA3>CA1 synapses, synaptic facilitation is reduced by half. At synapses of PV interneurons onto CA1 pyramidal neurons, the native rapid depression of this synapse is prevented. These results implicate regulation of Cav2.1 channels in determining the balance of synaptic facilitation vs. rapid depression. Excitation-inhibition ratio in the monosynaptic pathway vs. the disynaptic pathway from CA3 to CA1 neurons is greatly increased in IM-AA mice. As a consequence of this mutation, IM-AA mice have weakened long-term potentiation and severely impaired spatial learning and memory. Overall, these results show that biphasic regulation of Cav2.1 channels by calmodulin-like calcium sensor proteins contributes significantly to short-term synaptic facilitation and rapid depression, and show that this form of regulation is required for normal spatial learning and memory.
Dates
Created on October 24, 2018