Chloride channel protein 2

UniProt P51788 Organism Homo sapiens Gene CLCN2

Also known as: CLCN2

Function

Voltage-gated and osmosensitive chloride channel. Forms a homodimeric channel where each subunit has its own ion conduction pathway. Conducts double-barreled currents controlled by two types of gates, two fast glutamate gates that control each subunit independently and a slow common gate that opens and shuts off both subunits simultaneously. Displays inward rectification currents activated upon membrane hyperpolarization and extracellular hypotonicity. Contributes to chloride conductance involved in neuron excitability. In hippocampal neurons, generates a significant part of resting membrane conductance and provides an additional chloride efflux pathway to prevent chloride accumulation in dendrites upon GABA receptor activation. In glia, associates with the auxiliary subunit HEPACAM/GlialCAM at astrocytic processes and myelinated fiber tracts where it may regulate transcellular chloride flux buffering extracellular chloride and potassium concentrations. Regulates aldosterone production in adrenal glands. The opening of CLCN2 channels at hyperpolarized membrane potentials in the glomerulosa causes cell membrane depolarization, activation of voltage-gated calcium channels and increased expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Contributes to chloride conductance in retinal pigment epithelium involved in phagocytosis of shed photoreceptor outer segments and photoreceptor renewal. Conducts chloride currents at the basolateral membrane of epithelial cells with a role in chloride reabsorption rather than secretion (By similarity). Permeable to small monovalent anions with chloride > thiocyanate > bromide > nitrate > iodide ion selectivity (By similarity).

Classification

Family (Pfam): PF00654 Voltage_CLC
InterPro: CBS_dom_sf, Cl-channel-2, Cl-channel_core, Cl_channel_volt-gated, ClC
Functional cluster: Membrane Channels & Lipid-Anchored Proteins

Experimental structures · PDB · 8

7XF5 EM 3.90A
7XJA EM 3.50A
8GQU EM 3.50A
8TA2 EM 2.74A
8TA3 EM 2.46A
8TA4 EM 2.75A
8TA5 EM 2.76A
8TA6 EM 4.03A

A predicted model is available from AlphaFold.

Gene Ontology · 20

Disease associations

familial hyperaldosteronism type II MONDO:0011576
epilepsy, idiopathic generalized, susceptibility to, 11 MONDO:0011875
leukoencephalopathy with mild cerebellar ataxia and white matter edema MONDO:0014292

Drugs targeting this protein · 2

LUBIPROSTONE opener
COBIPROSTONE activator

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Chloride channel protein 2 5 shared papers
Hepatic and glial cell adhesion molecule 1 shared papers
H(+)/Cl(-) exchange transporter 5 1 shared papers
Chloride channel protein 2 1 shared papers
H(+)/Cl(-) exchange transporter 3 1 shared papers
H(+)/Cl(-) exchange transporter 6 1 shared papers
Hepatic and glial cell adhesion molecule 1 shared papers

Literature · 22 cited papers

CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism. Elife · 2024
Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function. Hum. Genet. · 2023
A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat. Genet. · 2018
CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat. Genet. · 2018
Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. · 2013
Regulation of ClC-2 gating by intracellular ATP. Pflugers Arch. · 2013
Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc. Natl. Acad. Sci. U.S.A. · 2012
GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. Neuron · 2012
PMID 19710717 Nat. Genet. · 2009
CLCN2 variants in idiopathic generalized epilepsy. Nat. Genet. · 2009
Clinical and genetic familial study of a large cohort of Italian children with idiopathic epilepsy. Brain Res. Bull. · 2009
… and 10 more in the literature graph

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