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

• Published in: Circulation research Vol. 109; no. 11; pp. 1250 - 1258
• Main Authors: Wang, Juejin, Thio, Sharon S.C., Yang, Sophia S.H., Yu, Dejie, Yu, Chye Yun, Wong, Yuk Peng, Liao, Ping, Li, Shengnan, Soong, Tuck Wah
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 11-11-2011; Lippincott Williams & Wilkins
• Subjects: Alternative splicing; Animals; Barium - metabolism; Biological and medical sciences; C-Terminus; Calcium - metabolism; Calcium channels; Calcium channels (voltage-gated); Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Cardiovascular system; Cell culture; Data processing; Excitation-contraction coupling; Exons; Exons - genetics; Fundamental and applied biological sciences. Psychology; Galectin 1 - physiology; galectin-1; Gene Knockdown Techniques; Humans; Hypertension; Ion Channel Gating; Lung; Muscle, Smooth - metabolism; Myocytes, Smooth Muscle - metabolism; Protein Binding; Protein Interaction Mapping; Protein Isoforms - metabolism; Protein Structure, Tertiary; Rats; RNA Splicing; siRNA; Smooth muscle; Two-Hybrid System Techniques; Vasoconstriction - genetics; Vasoconstriction - physiology; Vertebrates: cardiovascular system; Alternative splicing; Vertebrata; Mammalia; Calcium; Smooth muscle; Ionic channel; Circulatory system; vascular smooth muscle cell; Inorganic element; arterial constriction; Cay 1.2; galectin-1
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.248849

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. Our hypothesis is that Gal-1 interacts directly with CaV1.2 channel at the I–II loop to affect arterial constriction. 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 ICa,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. The above data indicated that Gal-1 regulates ICa,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.