Discovery of CLC transport proteins: cloning, structure, function and pathophysiology

Abstract

After providing a personal description of the convoluted path leading 25 years ago to the molecular identification of the Torpedo Cl − channel ClC-0 and the discovery of the CLC gene family, I succinctly describe the general structural and functional features of these ion transporters before giving a short overview of mammalian CLCs. These can be categorized into plasma membrane Cl − channels and vesicular Cl − /H + -exchangers. They are involved in the regulation of membrane excitability, transepithelial transport, extracellular ion homeostasis, endocytosis and lysosomal function. Diseases caused by CLC dysfunction include myotonia, neurodegeneration, deafness, blindness, leukodystrophy, male infertility, renal salt loss, kidney stones and osteopetrosis, revealing a surprisingly broad spectrum of biological roles for chloride transport that was unsuspected when I set out to clone the first voltage-gated chloride channel.

The Origin of Coupled Chloride and Proton Transport in a Cl–/H+ Antiporter

“…2,5,6 Defects in ClC proteins are known to cause several hereditary diseases, such as myotonia congenita, Dent’s disease, Bartter’s syndrome, osteopetrosis, and idiopathic epilepsy. 1,3,6 …”

Identification of Sidt2 as a lysosomal cation‐conducting protein

“…Potential counter ions could be negatively charged ions if transferred into the lysosomes or positively charged ions transported from the lysosomal lumen into the cytosolic compartment of the cell. Based on knock‐out studies the lysosomal proteins CLC‐7, a Cl − /H + antiporter, as well as cystic fibrosis transmembrane conductance regulator (CFTR) were already excluded as candidate proteins . Furthermore, direct measurement of the lysosomal acidification in the absence of Cl − suggests that the counter ion is a cation .…”

CLCN1 Myotonia congenita mutation with a variable pattern of inheritance suggests a novel mechanism of dominant myotonia

“…The daughter of one of the affected subjects (3.5) was an asymptomatic (or, alternatively, presymptomatic at age 7 years) carrier of the same variant. Another mildly affected individual (3.2) was not genotyped and neither was his aunt, who displayed mild calf and trapezius muscle hypertrophy.…”

“…Myotonia congenita (MC) is a hereditary chloride channel neuromuscular disorder . It is caused by mutations of the CLCN1 gene, which encodes ClC‐1, a chloride channel of the CLC channel/transporter family . ClC‐1 activity in skeletal muscle is important for maintaining resting potential .…”