C-terminal modulator controls Ca super(2+)-dependent gating of Ca sub(v)1.4 L-type Ca super(2+) channels

Tonic neurotransmitter release at sensory cell ribbon synapses is mediated by calcium (Ca super(2+)) influx through L-type voltage-gated Ca super(2+) channels. This tonic release requires the channels to inactivate slower than in other tissues. Ca sub(v)1.4 L-type voltage-gated Ca super(2+) channels (LTCCs) are found at high densities in photoreceptor terminals, and [alpha]1 subunit mutations cause human congenital stationary night blindness type-2 (CSNB2). Ca sub(v)1.4 voltage- dependent inactivation is slow and Ca super(2+)-dependent inactivation (CDI) is absent. We show that removal of the last 55 or 122 (C sub(122)) C-terminal amino acid residues of the human [alpha]1 subunit restores calmodulin-dependent CDI and shifts voltage of half-maximal activation to more negative potentials. The C terminus must therefore form part of a mechanism that prevents calmodulin- dependent CDI of Ca sub(v)1.4 and controls voltage-dependent activation. Fluorescence resonance energy transfer experiments in living cells revealed binding of C sub(122) to C-terminal motifs mediating CDI in other Ca super(2+) channels. The absence of this modulatory mechanism in the CSNB2 truncation mutant K1591X underlines its importance for normal retinal function in humans.