C-terminal modulator controls Ca²⁺-dependent gating of Ca_v1.4 L-type Ca²⁺ channels

Anamika Singh¹, Daniel Hamedinger², Jean-Charles Hoda¹, Mathias Gebhart¹, Alexandra Koschak¹, Christoph Romanin² & Jörg Striessnig¹

¹  Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie und Centrum für Molekulare Biowissenschaften Innsbruck, Universität Innsbruck, Peter-Mayrstr. 1/I, A-6020 Innsbruck, Austria.

²  Institut für Biophysik, Altenbergerstr. 69, Universität Linz, A-4040 Linz, Austria.

Tonic neurotransmitter release at sensory cell ribbon synapses is mediated by calcium (Ca²⁺) influx through L-type voltage-gated Ca²⁺ channels. This tonic release requires the channels to inactivate slower than in other tissues. Ca_v1.4 L-type voltage-gated Ca²⁺ channels (LTCCs) are found at high densities in photoreceptor terminals, and 1 subunit mutations cause human congenital stationary night blindness type-2 (CSNB2). Ca_v1.4 voltage-dependent inactivation is slow and Ca²⁺-dependent inactivation (CDI) is absent. We show that removal of the last 55 or 122 (C₁₂₂) C-terminal amino acid residues of the human 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_v1.4 and controls voltage-dependent activation. Fluorescence resonance energy transfer experiments in living cells revealed binding of C₁₂₂ to C-terminal motifs mediating CDI in other Ca²⁺ channels. The absence of this modulatory mechanism in the CSNB2 truncation mutant K1591X underlines its importance for normal retinal function in humans.

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