Phenomics of Cardiac Chloride Channels

Abstract

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.

Pro- and Antiarrhythmic Actions of Sulfonylureas: Mechanistic and Clinical Evidence

“…[61] Antagonism of such channels may be proarrhythmogenic (via abolished protection against focal triggered arrhythmias) or antiarrhythmic (via prevented reentrant arrhythmias). [62–65]…”

DIDS Reduces Ischemia/Reperfusion-Induced Myocardial Injury in Rats

“…However, the relationship between ion channels and ROS has not been elucidated in the process of I/R. In particular, anion channels such as chloride ion channel are reported to be involved in the generation of myocardial ischemia reperfusion arrhythmia [6,7]. Early application of anion channel blockers 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulphonic acid (SITS) and 5-nitro-2(3-phenylpropylamino) benzoic acid (NPPB) improves the ECG manifestation and reduces the degree of reperfusion arrhythmia [6].…”

The impact of Cystic Fibrosis Transmembrane Regulator Disruption on cardiac function and stress response

“…It was suggested that CFTR may play a role in maintaining the resting membrane potential and regulating the action potential duration, as well as in minimizing the depolarizing effect of Ca 2+ entry upon β-adrenergic stimulation [8]. An ex vivo study on isolated perfused hearts of CFTR-knockout mice also suggests the involvement of CFTR in mediating ischemic preconditioning [9].…”