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

Abstract

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.

9–Anthracene carboxylic acid is more suitable than DIDS for characterization of calcium-activated chloride current during canine ventricular action potential

“…Much information is already available about the contribution of various cationic currents to the cardiac AP, but anionic currents are much less well characterised (Duan 2009). One of these anionic currents is the calcium-activated chloride current (I Cl(Ca) ) (Eggermont 2004).…”

Voltage- and calcium-dependent gating of TMEM16A/Ano1 chloride channels are physically coupled by the first intracellular loop

“…A molecular understanding of the dual regulation of CaCCs by voltage and Ca 2+ has recently become possible with the discovery that Ano1 (TMEM16a) is an essential subunit of CaCCs. Ano1 can be gated by Ca 2+ (1,2), including epithelial secretion (3,4), sensory transduction and adaptation (5)(6)(7)(8), regulation of smooth muscle contraction (9), control of neuronal and cardiac excitability (10), and nociception (11). This myriad of functions has attracted attention for more than 25 years (12,13), but a lack of consensus regarding their molecular composition has stymied a mechanistic understanding of their gating.…”

Preassociated apocalmodulin mediates Ca 2+ -dependent sensitization of activation and inactivation of TMEM16A/16B Ca 2+ -gated Cl − channels

“…calmodulin | anoctamin1 | TMEM16A | calcium-activated chloride channel C alcium (Ca 2+ )-activated chloride (Cl -) channels (CaCCs) broadly expressed in mammalian cells regulate diverse physiological functions including: epithelial mucus secretion (1,2), neuronal excitability (3)(4)(5), smooth muscle contraction (6), olfactory transduction (7,8), and cell proliferation (9,10). Drugs targeting CaCCs are being pursued as therapies for hypertension, cystic fibrosis, asthma, and cancer (1,9,11).…”