Cellular and molecular physiology of volume-sensitive anion channels

Abstract

Maintenance of a constant cell volume in the face of osmotic stress is an evolutionarily ancient homeostatic process. Over the last two decades physiologists have gained an impressive understanding of the "volume-sensitive" channels, cotransporters, exchangers, metabolic pathways, and genes that are responsible for modulating intracellular solute content and cell volume. This review focuses on one part of this story, the characteristics and osmoregulatory functions of volume-sensitive anion channels. Three distinct types of swelling-activated anion channels have been observed and studied extensively in animal cells. These channels include 1) ClC-2, which is a member of the ClC family of voltage-gated anion channels, 2) an outwardly rectifying intermediate conductance channel, and 3) a large-conductance or "maxi" channel. In addition to these three channels, several other less well-characterized anion channels have been observed. This review discusses the electrophysiological and molecular biological characteristics and regulation of these channels. The possible roles different types of anion channels might play in cell volume homeostasis are also discussed.

ATP release from non-excitable cells

“…Numerous studies have demonstrated that cellular swelling activates a robust and large ATP release [42,[66][67][68]. This coincides with the fact that all cells in general react to cellular swelling with the activation of volume-sensitive anion channels [69]. Three discernible types of anion conductance are known to be activated by cellular swelling: ClC-2 channels, the volume-sensitive organic osmolyte and anion conductance (VSOAC; synonyms: VRAC, VSOR) [69] and a 'maxi' or large anion conductance.…”

“…Three discernible types of anion conductance are known to be activated by cellular swelling: ClC-2 channels, the volume-sensitive organic osmolyte and anion conductance (VSOAC; synonyms: VRAC, VSOR) [69] and a 'maxi' or large anion conductance. Whereas the molecular nature of VSOAC remains undefined, it has been suggested that the maxi or large anion conductance is identical to the mitochondrial voltage-dependent anion conductance (VDAC) and thus also present at the plasma membrane [69]. The ClC-2 channel is most likely not ATPpermeable, as discussed above.…”

“…VSOAC, for example, is permeable for sorbitol, various amino acids (e.g. taurine) and the methylamine betaine [69]. Okada has presented evidence that the maxi anion conductance (VDAC-like-VDACL) is a plasma membrane ATP-conductive pore in mammary cancer cells [70] and in macula densa cells [44], and follow-up work shows that this conductance is inhibited by internal arachidonic acid [71].…”

Cell volume regulation in mammalian oocytes and preimplantation embryos

“…organic osmolyte and anion channels,'' VSOAC) that are also permeable to a number of organic osmolytes. VRACs open upon cell swelling to allow the efflux of intracellular osmolytes (Strange et al, 1996;Okada, 1997). These channels are permeable to Cl À , allowing release of this inorganic osmolyte from cells, and also to a range of organic osmolytes ( Fig.…”

“…The molecular identity of these channels has been long sought, but remains elusive, as does the mechanism by which increased cell volume leads to channel opening (reviewed by Hoffmann et al, 2009). Nevertheless, VRACs have been detected functionally in a large range of cell types by the cell swelling-induced appearance of a characteristic outwardly rectifying anion current that can also be carried by various organic compounds (Strange et al, 1996;Okada, 1997). During recovery from cell volume increases, any negatively charged compound (e.g., Cl À ) must be accompanied by a cation to maintain electroneutrality.…”