Highly variable mRNA expression and splicing of L-type voltage-dependent calcium channel alpha subunit 1C in human heart tissues.
OBJECTIVE
The voltage-dependent L-type calcium channel alpha-subunit 1c (Cav1.2, CACNA1C) undergoes extensive mRNA splicing, leading to numerous isoforms with different functions. L-type calcium channel blockers are used in the treatment of hypertension and arrhythmias, but response varies between individuals. We have studied the interindividual variability in mRNA expression and splicing of CACNA1C, in 65 heart tissue samples, taken from heart transplant recipients.


METHODS
Splice variants were measured quantitatively by polymerase chain reaction in 12 splicing loci of CACNA1C mRNA. To search for functional cis-acting polymorphisms, we determined allelic expression ratios for total CACNA1C mRNA and several splice variants using marker single nucleotide polymorphisms in exon 4 and exon 30.


RESULTS
Total CACNA1C mRNA levels varied approximately 50-fold. Substantial splicing occurred in six loci generating two or more splice variants, some with known functional differences. Splice patterns varied broadly between individuals. Two heart tissues expressed predominantly the dihydropyridine-sensitive smooth muscle isoform of CACNA1C (containing exon 8), rather than the cardiac isoform (containing exon 8a). Lack of significant allelic expression imbalance, observed with total mRNA and several splice variants, argued against CACNA1C polymorphisms as a cause of variability. Taken together, highly variable splicing can cause profound phenotypic variations of CACNA1C function, potentially associated with disease susceptibility and response to L-type calcium channel blockers.
Wang
Danxin
D
Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Papp
Audrey C
AC
Binkley
Philip F
PF
Johnson
Julie A
JA
Sadée
Wolfgang
W
D000483:Alleles; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000235:genetics*; D017931:DNA Primers; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*
D020746:Calcium Channels, L-Type; D017931:DNA Primers; D012333:RNA, Messenger