The CLCAS: Proteins with ion channel, cell adhesion and tumor suppressor functions

Abstract

The CLCA family comprises a highly interesting group of proteins that have potentially very diverse functions within the cell. The physiological role of these proteins is yet to be established. They may be independent ion channels or regulatory subunits of such channels; the data obtained to date would be consistent with either interpretation. Results from lipid bilayer analysis using immunopurified protein are reasonably compelling, but because this is such a sensitive assay, the data could also be interpreted to mean that an otherwise undetectable but tightly bound channel remained associated with the purified protein when it was incorporated into the bilayer. Similarly, electrophysiological data obtained using the cloned CLCAs could suggest that the CLCAs either confer a novel Ca2+ sensitivity to a channel or activate an otherwise cryptic conductance. Expression of the bestrophin proteins is associated with the novel appearance of a linear Ca2+- and DIDS-sensitive current in HEK 293 cells. However, as shown by Greenwood and colleagues, co-expression of a CLCA with the BK channel β subunit resulted in a time-dependent conductance with an enhanced sensitivity for Ca 2+. One exciting possibility therefore is that the CLCAs may interact with the bestrophins or other proteins to generate the classical CaCC current profile. There may be more to this story: both the CLCAs and the bestrophins are reported to be expressed in the colon, despite several reports that Ca 2+-activated Cl- secretion does not occur in the gut. However, a residual Ca2+-activated Cl- current is found in some severely affected CF patients and in some intestinal cell models. What about the potential role of the CLCAs in cancer? There is certainly precedence in the literature for ion channel subunits to act as cell adhesion molecules, and for the involvement of ion channels in cancer progression, although in this latter role, channels are thought to aid rather than hinder the extreme changes in shape and volume that need to occur during invasion and proliferation. Why channels should be required for apoptosis is currently unknown, although it has been suggested that as the maintenance of a K+ gradient across the membrane is essential for cellular survival, K+ efflux may be a "disaster signal" that can trigger apoptosis. In this context, Cl - efflux would be required to maintain electroneutrality. As an increase in cell Ca2+ frequently precedes apoptosis, the commonality of Ca2+ signaling between these two ion transport pathways is intriguing. Whether the CLCAs need to act as ion channels/regulators in order to be tumor suppressors, or whether these two potential functions are totally independent of one another remains to be determined. Similarly, the reason underlying the seemingly specific up-regulation of CLCA1 in the airways of asthmatic patients and murine models of AHR is unclear; it may be required to promote mucus secretion as part of the inflammatory response of the airway, and perhaps serves a similar role in CF patients. In this case, it might be deleterious to increase expression of CLCA1 in the CF airway. In contrast, the mouse homolog of CLCA1 may act as a positive genetic modifier in long-living CF mice. These apparently contradictory data may suggest that up-regulation of the CLCA in mice may not necessarily translate to the human disease. Clearly the role of this protein in the airway as elsewhere, is an important issue that needs to be resolved.