Chloride channels

Chloride channels (CIC) are transmembrane ion channels (anion channels) of the cell membrane and the membrane of some intracellular organelles (e.g. the mitochondria), which have a specific and more or less selective conductivity for chloride ions. Chloride channels consist of protein complexes, comparable to the pore-forming protein complexes, the cation channels (see below ion channels) to which they have no structural relationship. CICs occur in both excitable and non-excitable cells (Park E et al. 2018). Four of the nine ClC proteins cloned so far are voltage-dependent anion channels (ClC-1, ClC-2, ClC-Ka and ClC-Kb), three work as transporters (ClC3, ClC-4 and ClC-5), for two other proteins (ClC-6 and ClC-7) the exact transport function is not yet known.

The ClC-α subunits have a complex membrane topology comprising 18 transmembrane segments. Two α subunits each combine to form a ClC channel (dimers), which in contrast to the cation channels forms two channel pores. Each pore is bounded by several asymmetrically arranged helices, which are at different angles to each other. Similar to certain voltage-dependent cation channels, a ClC dimer can be constructed from two identical or two different α subunits.

To maintain cell function, intracellular organelles must strictly regulate their ionic homeostasis. Any imbalance in ion concentration (which is essential for the volume regulation of intracellular organelles) can interfere with energy production, protein degradation (lysosomes), DNA replication (nucleus) or cellular signal transduction (endoplasmic reticulum). Ionic homeostasis is maintained by cation and anion channels and by ion transporters.

The movement of anions through the chloride channel is passive by diffusion. In contrast to the highly selective sodium, potassium or calcium channels, ClC channels are non-selective anion channels. As a result, a broad spectrum of different anions can permeate through these pores. Depending on the type of chloride channel, the activation (i.e. opening or closing) of the channel depends on various factors. Thus, the voltage-activated chloride channels react to the membrane potential of the cell. Other chloride channels react to swelling states of the cell, to the pH value, to the concentration of calcium ions, to the binding of ATP or the enzymatic cleavage of ATP. Furthermore, certain ligands are able to activate the CICs.

The calcium-activated chloride channel regulator 1 (CLCA1) belongs to a group of proteins that activate calcium-dependent chloride channels. It has been shown that chloride channel regulator 1 is involved in the pathogenesis of inflammatory respiratory diseases such as bronchial asthma (Hu D et al. 2019).

Diseases associated with dysfunction of ClC-2 include: retinal degeneration, Sjögren's syndrome, age-related cataracts, cystic fibrosis, epilepsy and diabetes mellitus (Gururaja Rao S et al. 2018).

Intact chloride conductivity is essential to maintain retinal function (Edwards et al., 2010). Thus, mutations in the ClCN-2 gene are associated with photoreceptor degenerations (Edwards MM et al. 2010).

The subfamily of the epithelial calcium-regulated chloride channels (E-ClC) are seen as an independent group.

1. Edwards MM et al (2010) Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an early stop mutation in CLCN2. Invest Ophthalmol Vis Sci 51: 3264-3272.
2. Gururaja Rao S et al (2018) Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology. Curr Protoc Pharmacol 80:11.21.1-11.21.17.
3. Hu D et al. (2019) The Emerging Role of Calcium- activated Chloride Channel Regulator 1 in Cancer. Anticancer Res 39:1661-1666.
4. Park E et al. (2018) Structure of the CLC-1 chloride channel from Homo sapiens. Elife 7:e36629.
5. Peters CJ et al. (2018) The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel. Neuron 97:1063-1077.