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Highly variable mRNA expression and splicing of L-type voltage-dependent calcium channel alpha subunit 1C in human

Danxin Wang1, Audrey C Papp, Philip F Binkley

  • 1Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.

Pharmacogenetics and Genomics
|September 27, 2006
PubMed

Insights

Interindividual variability in CACNA1C mRNA splicing creates diverse protein isoforms. This splicing variation, not genetic polymorphisms, significantly impacts L-type calcium channel function and drug response.

Area of Science:

  • Cardiovascular genetics
  • Molecular cardiology
  • Pharmacogenomics

Background:

  • The voltage-dependent L-type calcium channel alpha-subunit 1c (Cav1.2, CACNA1C) exhibits extensive mRNA splicing, producing functionally diverse isoforms.
  • L-type calcium channel blockers are crucial for treating hypertension and arrhythmias, yet patient responses exhibit significant interindividual variability.

Purpose of the Study:

  • To investigate the extent of interindividual variability in CACNA1C mRNA expression and splicing patterns.
  • To explore the role of CACNA1C splicing and potential polymorphisms in observed functional variations.

Main Methods:

  • Quantitative polymerase chain reaction (PCR) was employed to measure splice variants across 12 loci of CACNA1C mRNA in 65 human heart tissue samples.
  • Allelic expression ratios for total CACNA1C mRNA and specific splice variants were determined using single nucleotide polymorphisms (SNPs) in exons 4 and 30 to identify functional cis-acting polymorphisms.

Main Results:

  • Total CACNA1C mRNA levels displayed a 50-fold variation between individuals.
  • Significant alternative splicing was observed in six loci, yielding multiple splice variants with distinct functional implications.
  • Splice patterns varied considerably among individuals, with two samples predominantly expressing the smooth muscle isoform instead of the cardiac isoform.
  • The absence of significant allelic expression imbalance for total mRNA and splice variants suggested that CACNA1C polymorphisms are unlikely to be the primary source of variability.

Conclusions:

  • Highly variable CACNA1C mRNA splicing is a major driver of profound phenotypic variations in channel function.
  • These splicing-driven variations may contribute to differential disease susceptibility and variable responses to L-type calcium channel blocker medications.
Abstract

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