Perspective: Molecular Identity of the Outwardly Rectifying, Swelling-activated Anion Channel: Time to Reevaluate pICln

Cells respond to swelling by activating anion and cation channels that allow the passive loss of inorganic ions and organic solutes. Net solute efflux accompanied by osmotically obliged water functions to return cell volume towards its original value, a process termed regulatory volume decrease. An apparently ubiquitous response to swelling in vertebrate cells is activation of an outwardly rectifying an-ion current termed I Cl.swell. The general characteristics of this current include an Eisenman type I anion perme-ability sequence (I Ϫ Ͼ Br Ϫ Ͼ Cl Ϫ Ͼ F Ϫ), modest outward rectification, voltage-dependent inactivation at potentials above E Cl , inhibition by a wide variety of compounds , including conventional anion transport inhib-itors, and block by extracellular nucleotides such as ATP (reviewed by Strange et al., 1996; Okada, 1997). The degree of rectification, voltage sensitivity, and phar-macology can vary somewhat between different cell types. It is not clear whether the differences observed reflect the existence of distinct channels, or whether they are due to experimental and/or physiological variables. For example, channel voltage sensitivity is altered by in-tracellular Mg 2 ϩ concentration (Okada, 1997), the trans-membrane Cl Ϫ gradient, and by the presence of foreign anions in the extracellular solution (Meyer and Korb-macher, 1996; Okada, 1997; my unpublished observations). In this article, I will assume for the sake of simplicity that I Cl.swell arises from the activity of a single channel type or a family of closely related channels. The channel responsible for I Cl.swell has been referred to by a variety of names, including VRAC (volume regulated anion channel) and VSOR (volume expansion-sensing outwardly rectifying anion channel). Another name for the channel is VSOAC (volume-sensitive organic osmolyte/anion channel), which was coined to reflect the putative role it plays in the transport of organic anions and electroneutral organic osmolytes (Strange et al., 1996; Kirk and Strange, 1998). To avoid confusion , I will refer to the channel in this paper simply as the I Cl.swell channel. The route to the molecular identification of the I Cl.swell channel has been an elusive and exceptionally confusing one. The first purported molecular sighting of the channel was made in 1992. Valverde et al. (1992) and Gill et al. (1992) proposed that P-glycoprotein, the product of the multidrug resistance-1 gene, functions as both a drug transporter and the I Cl.swell channel. However, numerous laboratories have been unable to reproduce the findings of these investigators and …