Phenomics of cardiac chloride channels: the systematic study of chloride channel function in the heart

Recent studies have identified several chloride (Cl-) channel genes in the heart, including CFTR, ClC-2, ClC-3, CLCA, Bestrophin, and TMEM16A. Gene targeting and transgenic techniques have been used to delineate the functional role of cardiac Cl- channels in the context of health and disease. It has been shown that Cl- channels may contribute to cardiac arrhythmogenesis, myocardial hypertrophy and heart failure, and cardioprotection against ischaemia-reperfusion. The study of physiological or pathophysiological phenotypes of cardiac Cl- channels, however, may be 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 multi-protein complexes of the Cl- channel subproteome and similar phenotypes can be attained from alternative protein pathways within cellular networks, which are influenced by genetic and environmental factors. Therefore, 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 (such as gene knockouts or knockins) under the scope of genome/proteome/phenome, may provide a more complete understanding of the integrated function of each cardiac Cl- channel in the context of health and disease.