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C-terminal splicing reveals intramolecular gating modulation in CaV1.3 L-type Ca2+ channels

Neuronal excitability and pace-making in the sinoatrial node are controlled by low-voltage activated CaV1.3 L-type Ca2+ channels. We recently found that in related CaV1.4 channels a highly-structured distal C-terminal motif (CTM) modulates voltage- and Ca2+-dependent gating (CDI). In CaV1.3, C-terminal splicing leads to a full-length (CaV1.3L) and at least 1 short (CaV1.3S) splice form. If a CTM would also modulate CaV1.3 gating it would be present in CaV1.3L but not CaV1.3S variants. We therefore compared the biophysical properties of CaV1.3L or CaV1.3S coexpressed with β3 + α2δ-1 in tsA-201 cells using the whole-cell patch-clamp technique. CaV1.3S channels activated at more negative potentials compared to CaV1.3L (~ -10 mV, p < 0.0001), inactivated faster (p < 0.01) and showed more CDI (p < 0.01). These changes resulted in a decreased window current shifted to more hyperpolarized potentials likely to cause a reduction in the channels' dynamic range. Removal of the C-terminal 158 (CaV1.3Δ1158) or 76 amino acids was sufficient to induce gating properties similar to CaV1.3S. FRET experiments revealed interaction of the last 158 amino acids (C158) to a proximal C-terminal domain in CaV1.3L. Coexpression of C158 with CaV1.3Δ1158 completely restored CaV1.3L gating properties confirming this protein interaction. Thus CaV1.3 channel gating is under control of the distal C-terminus allowing alternative splicing to fine-tune channel activity and adapt channel function to physiological needs.

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Correspondence to Alexandra Koschak.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Singh, A., Gebhart, M., Fritsch, R. et al. C-terminal splicing reveals intramolecular gating modulation in CaV1.3 L-type Ca2+ channels. BMC Pharmacol 7 (Suppl 2), A11 (2007).

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