Splicing for alternative structures of Ca1.2 Ca channels in cardiac and smooth muscles

Abstract

An estimate of up to 60% of genes are subjected to alternative splicing, and 15% of human genetic diseases are associated with mutation of the splice sites [Krawczak M, Reiss J, and Cooper DN. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 1992; 90: 41-54; Cooper TA, and Mattox W. The regulation of splice-site selection, and its role in human disease. Am J Hum Genet 1997; 61: 259-66; Modrek B and Lee CJ. Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss. Nat Genet 2003; 34: 177-80; Modrek B, Resch A, Grasso C, and Lee C. Genome-wide detection of alternative splicing in expressed sequences of human genes. Nucleic Acids Res 2001; 29: 2850-9; Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860-921] . The molecular diversity of alternatively spliced transcripts provides templates for a myriad of protein structures that are potentially crucial to sustaining the complexity of human physiology. The extensive alternative splicing of the alpha(1)1.2-subunit of the L-type Ca(v)1.2 channel, producing splice variants with distinct electrophysiological and pharmacological properties, would impact directly on the function of the cardiovascular system. Cell-selective expression of Ca(v)1.2 channels containing a specific alternatively spliced exon increases the functional variations for specific cellular activities in response to changing physiological signals. However, the regulation or control of the alpha(1)1.2-subunit alternative splicing machinery is unknown, and the role of numerous splice variants expressed in a cell is a mystery. A systematic and concerted effort is required to determine all the possible combinations of alternatively spliced exons in alpha(1)1.2-subunits in smooth and cardiac muscles. This will provide useful information to monitor changes on the usage of the entire suite of alternatively spliced exons to help relate altered Ca(v)1.2 channel function to physiology and disease.

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

“…Another specific feature of L-type Ca 2+ channels is that their population is not homogeneous because of the occurrence of alternatively spliced isoforms (Koch et al, 1990). Among the 55 known human Ltype Ca 2+ channel exons 19 undergo alternative splicing and display differences in tissue distribution, physiology, pharmacology and disease-related up-and/or down-regulation (Liao et al, 2005;Tang et al, 2007;Tiwari et al, 2006). Some of these isoforms were dominant in aorta (> 50%) and less abundant in heart (<5%).…”

Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy

“…Several genes have been shown to be misspliced in DM1 cardiac tissues, such as TNNT2, KCNAB1, Titin, and ALP (21) as well as FXR1h, identified in the present study. Mutations within a large number of ion channels have been shown to cause familial forms of arrhythmias, and these genes often express multiple isoforms by alternative splicing (43,44). The effect of EpA960(R) RNA expression on cardiac function is independent of the arrhythmias and indicates that CUG repeat RNA induces a functional defect within the myocardium.…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…Deletion of α 1C subunit in mice resulted in embryonic lethality [11], and conditional knockout of smooth muscle α 1C (SMAKO) lowered the arterial blood pressure in mice [12]. Recently, multiply alternative splicing events have been found in CACNA1C , which optimize the functions of Ca V 1.2 channel [13,14]. Moreover, alternative splicing in Ca V 1.2 channels make some roles in several cardiovascular diseases, including cardiac arrhythmia [15–17].…”

“…For example, alternative splicing, one of most important mechanisms of post-transcriptional modification [130,131], generates more than 20 alternative spliced exons in α 1C mRNA, which forms many variants of α 1C [14,60,132]. It has been indicated the mutations in these alternative spliced exons of LTCC can also attribute to the abnormal cardiac excitation [61,62,126].…”