C-terminal modulator controls Ca2+-dependent gating of Ca(v)1.4 L-type Ca2+ channels.
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(v)1.4 L-type voltage-gated Ca2+ channels (LTCCs) are found at high densities in photoreceptor terminals, and alpha1 subunit mutations cause human congenital stationary night blindness type-2 (CSNB2). Ca(v)1.4 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 alpha1 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(v)1.4 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.
Singh
Anamika
A
Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie und Centrum für Molekulare Biowissenschaften Innsbruck, Universität Innsbruck, Peter-Mayrstr. 1/I, A-6020 Innsbruck, Austria.
Hamedinger
Daniel
D
Hoda
Jean-Charles
JC
Gebhart
Mathias
M
Koschak
Alexandra
A
Romanin
Christoph
C
Striessnig
Jörg
J
D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002147:Calmodulin / Q000494:pharmacology; D002460:Cell Line; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal / Q000379:methods; D020125:Mutation, Missense / Q000235:genetics; D018408:Patch-Clamp Techniques; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
C113330:CACNA1F protein, human; D020746:Calcium Channels, L-Type; D002147:Calmodulin; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D002118:Calcium