Clc-2 Case Study

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Discovered in the early 1990s, ClCs are involved in a many physiological processes including regulating resting membrane potential in skeletal muscle, facilitation of transepithelial chloride reabsorption in kidneys and control of pH and chloride concentration in intracellular compartments through coupled Cl-/H+ exchange mechanisms [1]. The family consists of nine members, with ClC-1 and ClC-2 giving rise to substantial chloride currents, when expressed in Xenopus oocytes or transfected cells [2]. The ClC-1 channel is homodimer with both the N- and C-termini located on the cytosolic side, which is encoded by the CLCN1 gene, and the channel itself is estimated to contribute ~80% of the resting membrane potential conductance. ClC-1 …show more content…

ClC-1 is thought to be the main chloride channel responsible for muscle cell repolarisation, although not all ‘whole muscle’ experiments support this – the majority of muscle cell repolarisation is attributable to action of voltage-gated K+ channels, but ClC-1 channel activity is nonetheless significant. The physiological role of ClC-1 is demonstrated by the pathophysiology of myotonia congenital – which occurs from mutations in the CLCN1 gene. ClC-1 channel inhibitors, such as A-9-C and CPP, can induce myotonia – a condition in which a single action potential (AP) at the neuromuscular junction causes repetitive AP firing, and thus delayed muscle relaxation. Immunohistochemical evidence suggests ClC-1 is concentrated in the sarcolemmal membrane rather than the t-tubular membrane, which was not expected – as repeated muscle stimulation accumulates K+ in the t-tubular membrane, hence it would be expected to find the majority of chloride conductance localised here (Figure 2). This differs greatly from previous physiological localisation of ClC-1, which suggested up to 80% of chloride conductance may be associated with the t-tubular membrane [6]. Interestingly, no clear physiological significance of ClC-1 channels has been detected in other tissues [5].

Figure 2 – Schematic of skeletal muscle fibre following repeated stimulation

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