Functional effects of a lethal mutation (R1667P) in the voltage-sensing S4 α-helix of Repeat IV of CaV2.1

Abstract

Ca2+ influx via P/Q-type CaV2.1 voltage-gated Ca2+ channels supports neurotransmitter release at central synapses. Point mutations in CACNA1A, the gene encoding CaV2.1, cause a spectrum of neurological disorders. In particular, an arginine to proline substitution at position 1667 (R1667P) gives rise to an ultimately fatal syndrome characterized by seizures, generalized hypotonia, congenital ataxia and cerebral edema. R1667 is the third basic residue lining the S4 voltage-sensing α-helix in Repeat IV of the channel.