Splice Variant Specific Modulation of CaV1.2 Calcium Channel by Galectin-1 Regulates Arterial Constriction

Published on Nov 11, 2011in Circulation Research17.367
· DOI :10.1161/CIRCRESAHA.111.248849
Juejin Wang5
Estimated H-index: 5
(NUS: National University of Singapore),
Sharon S.C. Thio1
Estimated H-index: 1
+ 6 AuthorsTuck Wah Soong41
Estimated H-index: 41
Sources
Abstract
Rationale: CaV1.2 channels are essential for excitation–contraction coupling in the cardiovascular system, and alternative splicing optimizes its role. Galectin-1 (Gal-1) has been reported to regulate vascular smooth muscle cell (VSMC) function and play a role in pulmonary hypertension. We have identified Gal-1 multiple times in yeast 2-hybrid assays using the CaV1.2 I–II loop as bait. Objective: Our hypothesis is that Gal-1 interacts directly with CaV1.2 channel at the I–II loop to affect arterial constriction. Methods and Results: Unexpectedly, Gal-1 was found to selectively bind to the I–II loop only in the absence of alternatively spliced exon 9*. We found that the current densities of CaV1.2Δ9* channels were significantly inhibited as a result of decreased functional surface expression due to the binding of Gal-1 at the export signal located on the C-terminus of exon 9. Moreover, the suppression of Gal-1 expression by siRNA in rat A7r5 and isolated VSMCs produced the opposite effect of increased I Ca,L. The physiological significance of Gal-1 mediated splice variant-specific inhibition of CaV1.2 channels was demonstrated in organ bath culture where rat MAs were reversibly permeabilized with Gal-1 siRNA and the arterial wall exhibited increased K+-induced constriction. Conclusion: The above data indicated that Gal-1 regulates I Ca,L via decreasing the functional surface expression of CaV1.2 channels in a splice variant selective manner and such a mechanism may play a role in modulating vascular constriction.
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