Phenomics of Cardiac Chloride Channels

Forward genetic studies have identified several chloride (Cl − ) channel genes, including CFTR , ClC‐2 , ClC‐3, CLCA , Bestrophin, and Ano1 , in the heart. Recent reverse genetic studies using gene targeting and transgenic techniques to delineate the functional role of cardiac Cl − channels have shown that Cl − channels may contribute to cardiac arrhythmogenesis, myocardial hypertrophy and heart failure, and cardioprotection against ischemia reperfusion. The study of physiological or pathophysiological phenotypes of cardiac Cl − channels, however, is complicated by the compensatory changes in the animals in response to the targeted genetic manipulation. Alternatively, tissue‐specific conditional or inducible knockout or knockin animal models may be more valuable in the phenotypic studies of specific Cl − channels by limiting the effect of compensation on the phenotype. The integrated function of Cl − channels may involve multiprotein complexes of the Cl − channel subproteome. Similar phenotypes can be attained from alternative protein pathways within cellular networks, which are influenced by genetic and environmental factors. The phenomics approach, which characterizes phenotypes as a whole phenome and systematically studies the molecular changes that give rise to particular phenotypes achieved by modifying the genotype under the scope of genome/proteome/phenome, may provide more complete understanding of the integrated function of each cardiac Cl − channel in the context of health and disease.