1.2 calcium channels are the principal proteins involved in electrical, mechanical, and/or signaling functions of the cell. 1.2 couples membrane depolarization to the transient increase in intracellular Ca2+ concentration that is a trigger for muscle contraction and CREB-dependent transcriptional activation. The CACNA1C gene coding for the 1.2 pore-forming subunit is subject to extensive alternative splicing. This review is the first attempt to follow the association between cell proliferation, 1.2 expression and splice variation, and atherosclerosis. Based on insights into the association between the atherosclerosis-induced molecular remodeling of 1.2, proliferation of vascular smooth muscle cells, and CREB-dependent transcriptional signaling, this review will give a perspective outlook for the use of the CACNA1C exon skipping as a new potential gene therapy approach to atherosclerosis. 1. Introduction It has been long known that Cav1.2 calcium channel blockers inhibit human brain tumor [1], pancreatic cancer [2, 3], breast cancers [4] and small cell lung cancer [5] because they inhibit cell proliferation and DNA synthesis. Correlation between the oncogenic transformation and expression of both Cav1.2 and Cav3 channels was demonstrated in spontaneously immortalized 3T3 fibroblasts [6, 7] suggesting that both types of calcium channels may play a role in cell proliferation. Indeed, studies showed that Cav3 (T-type) calcium channels regulate proliferation, for example, of BC3H1 cells [8], vascular smooth muscle (VSM) cells [9], and glioma, neuroblastoma, and neuroblastoma × glioma hybrid cells [10]. Unlike the majority of cells, including the listed ones, normal human fibroblasts express only Cav1.2 [11]. The pore-forming subunit of this channel was cloned from human fibroblasts and identified as a “short” (exon 1) isoform of the -coding gene CACNA1C [12]. A variety of Cav1.2 calcium channel blockers, including dihydropyridines (DHPs) nifedipine and nicardipine, as well as diltiazem and verapamil inhibit cell proliferation and DNA synthesis in fibroblasts [13]. Thus, human fibroblast is an excellent cell type to study the roles of Cav1.2 in proliferation not complicated by expression of other Cav genetic variants, cell transformation, and/or differentiation. 2. Ca 1.2 and Proliferation of Normal Human Fibroblasts Our earlier studies performed on normal human diploid fibroblasts have revealed a number of important features that point to the plasticity of the Cav1.2 expression in response to cell culture conditions, including cell-cell contact inhibition,
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