Amazing chloride channels: an overview

Abstract

This review describes molecular and functional properties of the following Cl- channels: the ClC family of voltage-dependent Cl- channels, the cAMP-activated transmembrane conductance regulator (CFTR), Ca2+ activated Cl- channels (CaCC) and volume-regulated anion channels (VRAC). If structural data are available, their relationship with the function of Cl- channels will be discussed. We also describe shortly some recently discovered channels, including high conductance Cl- channels and the family of bestrophins. We illustrate the growing physiological importance of these channels in the plasma membrane and in intracellular membranes, including their involvement in transepithelial transport, pH regulation of intracellular organelles, regulation of excitability and volume regulation. Finally, we discuss the role of Cl- channels in various diseases and describe the pathological phenotypes observed in knockout mice models.

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

“…A key study that proposed a mechanistic link between astrocytic swelling and brain damage has been done by Kimelberg and co-workers, who found that exposure of cultured astrocytes to hypoosmotic media triggers massive release of several cytosolic amino acids, including glutamate and aspartate [52]. The swellingactivated amino acid release permeability pathway is sensitive to a number of anion channel blockers, and has strong similarities to the already mentioned swelling-activated anion channel VRAC [22,24,[52][53][54]. Since electrophysiological studies confirmed that VRAC possesses measurable permeability to glutamate and aspartate [55][56][57], this channel has long been considered a hypothetical pathway for pathological release of excitotoxins from swollen cells [13,45,46].…”

“…In spite of the extensive search in the field, the molecular identity of VRAC remains unknown [24,58]. Therefore any studies designed to explore the physiological and pathological roles for this channel have to rely on pharmacological tools.…”

“…Tamoxifen, which is frequently described as the potent and selective inhibitor of the VRAC, is completely ineffective in neuronal cells and blocks a number of other anion and cation channels [60][61][62]. Other VRAC blockers include 1,9-dideoxyforskolin, niflumic acid, calaxarenes, and phloretin [23,24]. The most selective VRAC inhibitor identified so far is the ethacrynic-acid derivative DCPIB (IC 50 =4 μM) [63].…”

“…However, a recent study by Inoue and Okada demonstrated that, in cortical slices and cultured neurons, glutamate-induced Cl − fluxes are largely mediated by the VOLUME-SENSITIVE OUTWARDLY RECTIFYING (VSOR) CL − CHANNEL [21]. VSOR is also known in the literature as VOLUME-SENSITIVE ORGANIC OSMOLYTE-ANION CHANNEL (VSOAC) or VOLUME-REGULATED ANION CHANNEL (VRAC) [22][23][24]. In this review the acronym VRAC will be used.…”

Cl− Channels and Transporters in Sperm Physiology

“…The molecular identity of the Cl − channels involved in volume regulation is not established. Candidates such as ClC-2 (CLCN2) and ClC-3 (CLCN3) have been proposed to play a role in somatic cells (Furst et al 2002 ;Nilius and Droogmans 2003 ); however, their function is still controversial (Sardini et al 2003 ). Interestingly, CLCN3 was detected by Western blot and localized to the sperm tail by immunofl uorescence (Yeung et al 2005 ).…”