Disease relevance of CLCN1

• The pleiotropic effects of cystic fibrosis (CF) result from the mislocalization or inactivity of an apical membrane chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR) [1].
• OBJECTIVE: To develop a molecular genetic test to detect the mutant skeletal muscle chloride channel (CIC-1) allele that causes myotonia congenita in Miniature Schnauzers and to analyze the relationship of affected and carrier dogs [2].

High impact information on CLCN1

• The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is regulated by phosphorylation of the R domain and ATP hydrolysis at two nucleotide-binding domains (NBDs) [3].
• This suggests that dysidenin does not act as a chloride channel inhibitor or a Na+ ionophore [4].
• In voltage clamp they showed abundant calcium-activated chloride current and spontaneous transient inward currents which could be blocked by chloride channel blockers [5].
• 3. Experiments were performed to determine whether the molecular form of the volume-regulated chloride channel (ClC-3) is expressed in pulmonary and renal arteries [6].
• Quantitative RT-PCR confirmed expression of ClC-3 in both types of smooth muscle [6].

Biological context of CLCN1

• Mutations in a skeletal muscle voltage-dependent chloride channel, CIC-1, have been identified as the molecular genetic basis for the syndrome in humans, and in two well characterized animal models of the disease: the myotonic goat, and the arrested development of righting (adr) mouse [7].
• The combination of 4-AP plus ryanodine, low chloride, or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (chloride channel blocker) completely eliminated the notch and all rate dependence of the early phases of the action potential, making RVE and LVE indistinguishable [8].

Anatomical context of CLCN1

• These observations are consistent with the hypothesis that a plasma membrane protein related to glycine-gated chloride channel receptors plays a significant role in cell injury, but indicate that the mechanisms of injury and protection by compounds active in this system are not related to chloride fluxes [9].
• An inwardly rectifying chloride channel in ragweed-sensitized canine tracheal epithelial cells [10].
• Actions of putative chloride channel blocking agents on canine lower esophageal sphincter (LES) [11].
• Inflation depolarized dog atrial myocytes when the recording electrodes contained either 17 or 42 mM Cl-. The depolarization coincided with activation of I(Cl,swell) and was antagonized by the chloride-channel blocker niflumic acid [12].

Associations of CLCN1 with chemical compounds

• These effects have been attributed to interactions with membrane proteins related to CNS glycine gated chloride channel receptors [9].
• Two classes of compounds showed cytoprotective activity in this system: (1) ligands at chloride channel receptors, such as glycine, strychnine and avermectin B1a; (2) chloride channel blockers, including cyanotriphenylboron and niflumic acid, both of which are known to bind to channel domains of CNS glycine receptors [9].
• The increased unidirectional Cl- flux induced by high K+ exposure was inhibited by luminal exposure to diphenylamine-2-carboxylic acid (DPC) or other chloride channel blockers, but was not inhibited by loop diuretics [13].
• Inhibitors of chloride channel activity such as DIDS and NPPB reduced acidification [14].

Other interactions of CLCN1

• ClC-3 expression was 76.4 % of beta-actin in renal artery and 48.0 % of beta-actin in pulmonary artery [6].

Analytical, diagnostic and therapeutic context of CLCN1

• In particular, a potassium and a chloride channel appeared in the recordings more frequently than other channels, and this allowed a more detailed study of their properties in the inside-out configuration of the patch-clamp technique [15].
• RESULTS: Enzyme digestion of PCR products of the normal CIC-1 allele resulted in 3 fragments of 175, 135, and 30 bp, whereas PCR products of the mutant allele resulted in fragments of only 175 and 165 bp [2].

References