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  • Meeting abstract
  • Open Access

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

  • 1,
  • 1,
  • 2,
  • 1,
  • 1,
  • 2,
  • 1 and
  • 1Email author
BMC Pharmacology20077(Suppl 2):A11

https://doi.org/10.1186/1471-2210-7-S2-A11

Published: 14 November 2007

Keywords

  • Protein Interaction
  • Alternative Splice
  • Channel Activity
  • Negative Potential
  • Neuronal Excitability

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.

Authors’ Affiliations

(1)
Pharmacology and Toxicology, Department of Pharmacy, University of Innsbruck, Austria
(2)
Department of Biophysics, University of Linz, Austria

Copyright

© Singh et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

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