Abstract
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. Cav1.4 L-type voltage-gated Ca2+ channels (LTCCs) are found at high densities in photoreceptor terminals, and α1 subunit mutations cause human congenital stationary night blindness type-2 (CSNB2). Cav1.4 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 α1 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 Cav1.4 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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Acknowledgements
We thank O. Strauß for comments on the manuscript, and G. Pelster and J. Aldrian for technical assistance. Wild-type and mutant calmodulin were gifts from J. Adelman (Vollum Institute, Portland, Oregon). This work was supported by the Austrian Science Funds (P-17109 and P-17159 to J.S.; P-15387 and P-16537 to C.R.) and by the University of Innsbruck.
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Supplementary information
Supplementary Fig. 1
Sequence alignment of C-terminal tails of neuronal Cav1 L-type channels. (PDF 578 kb)
Supplementary Fig. 2
Comparison of K1591X channels containing β2a or β3 subunits. (PDF 110 kb)
Supplementary Fig. 3
Inactivation properties of Cav 1.4ΔC122. (PDF 98 kb)
Supplementary Fig. 4
Ca2+ dependence of C122-CFP binding to peptide YFP-PreIQ-IQ-PostIQ in intact HEK-293 cells. (PDF 74 kb)
Supplementary Fig. 5
Potential molecular mechanism for CDI modulation by C122. (PDF 45 kb)
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Singh, A., Hamedinger, D., Hoda, JC. et al. C-terminal modulator controls Ca2+-dependent gating of Cav1.4 L-type Ca2+ channels. Nat Neurosci 9, 1108–1116 (2006). https://doi.org/10.1038/nn1751
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DOI: https://doi.org/10.1038/nn1751
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