The chloride-hydrogen antiporter facilitates the exchange of chloride ions for hydrogen ions across plasma membranes, thus playing a critical role in maintaining acid-base balance and chloride homeostasis. It is found in various tissues, including the gastrointestinal tract, kidneys, and pancreas. The well-known chloride-hydrogen antiporters belong in the CLC family, which have isoforms from CLC-1 to CLC-7, each with a distinct tissue distribution. Their structure involves two CLC proteins coming together to form a homodimer or a heterodimer where both monomers contain an ion translocation pathway. CLC proteins can either be ion channels or anion-proton exchangers, so CLC-1 and CLC-2 are membrane chloride channels, while CLC-3 through CLC-7 are chloride-hydrogen exchangers.
CLC-4 is a member of the CLC family that is prominent in the brain, but is also located in the liver, kidneys, heart, skeletal muscle, and intestine. It likely resides in endosomes and participates in their acidification, but can also be expressed in the endoplasmic reticulum and plasma membrane. Its roles are not entirely clear, but CLC-4 has been found to possibly participate in endosomal acidification, transferrin trafficking, renal endocytosis, and the hepatic secretory pathway.
CLC-5 is one of the best-studied members of this protein family. It shares 80% of its amino acid sequence with CLC-3 and CLC-4, but it is mainly found in the kidney, especially in the proximal tubule, collecting duct, and ascending limb of the loop of Henle. It functions to transport substances through the endosomal membrane, so it is crucial for pinocytosis, receptor-mediated endocytosis, and endocytosis of plasma membrane proteins from the apical surface.
CLC-7 is another example of a CLC family protein. It is ubiquitously expressed as the chloride-hydrogen antiporter in lysosomes and in the ruffled border of osteoclasts. CLC-7 may be important for regulating to concentration of chloride in lysosomes. It is associated with a protein called Ostm1, forming a complex that allows CLC-7 to carry out its functions. For example, these proteins are crucial to the process of acidifying the resorption lacuna, which enables bone remodeling to occur.
CLC-4 has been connected with mental retardation involving seizure disorders, facial abnormalities, and behavior disorders. Studies found frameshift and missense mutations in patients exhibiting these symptoms. Because these symptoms were mostly exhibited in males, with less severe pathology in females, it is likely X-linked. Studies done on animal models have also shown the possibility of a connection between nonfunctional CLC-4 and impaired neural branching of hippocampus neurons.
Defects in the CLC-5 gene were shown to be the cause of 60% of cases of Dents disease, which is characterized by tubular proteinuria, formation of kidney stones, excess calcium in the urine, nephrocalcinosis, and chronic kidney failure. This is caused by abnormalities that occur in the endocytosis process when CLC-5 is mutated. Dents disease itself is one of the causes of Fanconi syndrome, which occurs when the proximal convoluted tubules of the kidney do not perform an adequate level of reabsorption. It causes molecules produced by metabolic pathways, such as amino acids, glucose, and uric acid to be excreted in the urine instead of being reabsorbed. The result is polyuria, dehydration, rickets in children, osteomalacia in adults, acidosis, and hypokalemia.
CLC-7's role in osteoclast function was revealed by studies on knockout mice that developed severe osteopetrosis. These mice were smaller, had shortened long bones, disorganized trabecular structure, a missing medullary cavity, and their teeth did not erupt. This was found to be caused by deletion mutations, missense mutations, and gain-of-function mutations that sped up the gating of CLC-7. CLC-7 is expressed in almost every neuronal cell type, and its loss led to widespread neurodegeneration in mice, especially in the hippocampus. In longer-lived models, the cortex and hippocampus had almost entirely disappeared after 1.5 years. Finally, because of its importance in lysosomes, altered expression of CLC-7 can lead to lysosomal storage disorders. Mice with a mutation introduced to the CLC-7 gene developed lysosomal storage disease and retinal degeneration.