Hypertonicity‐induced cation channels

Abstract

Whenever studied in a quantitative fashion, hypertonicity-induced cation channels (HICCs) are found to be the main mediators of regulatory volume increase. In most instances, these channels are either inhibited by amiloride (but insensitive to Gd3+ and flufenamate) or they are efficiently blocked by Gd3+ and flufenamate (but insensitive to amiloride). Of note, however, from two preparations so far a mixed type of pharmacology has also been reported. Whereas the ion selectivity of amiloride-sensitive HICCs has not been studied in much detail yet, amiloride-insensitive channels are either equally permeable to Na+, K+, Cs+ and Li+ but impermeable to N-methyl-D-glucamine (NMDG+) or they exhibit a permeability to Li+ and NMDG+ that amounts to some 50% when compared with that of Na+. Also in this respect, however, some peculiarities do exist. Concerning the actual molecular correlate, evidence was reported that HICCs may be related to the (amiloride-sensitive) epithelial Na+ channel and/or to transient receptor potential channels. Recent findings suggest that HICCs may contribute to cell proliferation, just as the K+ channels that are employed in regulatory volume decrease are mediators of the opposing process, i.e. apoptosis.

Channels and Volume Changes in the Life and Death of the Cell

“…In contrast to RVD, in which the corrective fluxes of osmolytes permeate essentially across ion channels and diffuse pathways for organic osmolytes, in RVI, channels play only a minor role, and the regulatory process is essentially accomplished by cotransporters and exchangers. It has been proposed that unidentified hypertonicity-activated cation channels participate in RVI (Wehner et al, 2006). A study in HeLa cells (Wehner et al, 2006) showing RVI reduction by SKF-96365, a blocker of TRP channels, raised the question of whether the hypertonicity-induced cation channels are actually TRP channels, and recent evidence pointed to TRPM2 as the channel involved.…”

“…It has been proposed that unidentified hypertonicity-activated cation channels participate in RVI (Wehner et al, 2006). A study in HeLa cells (Wehner et al, 2006) showing RVI reduction by SKF-96365, a blocker of TRP channels, raised the question of whether the hypertonicity-induced cation channels are actually TRP channels, and recent evidence pointed to TRPM2 as the channel involved. A recent report, also in HeLa cells (Numata et al, 2012), showed that nucleotides adenosine diphosphate ribose (ADPr) and cyclic ADPr, reported as typical TRPM2 activators (Pedersen et al, 2005;Pedersen and Nilius, 2007), generate cation currents similar to those elicited by hypertonicity, previously known as hypertonicityactivated cation channels.…”

Physiology of Cell Volume Regulation in Vertebrates

“…Shrinkage-induced activation of cation channels can be demonstrated in many cell types, and hypertonicityinduced cation channels (HICCs) have proven to be a major mechanism of RVI in some cells (817,860,1079,1082,1083). Pharmacologically, three types of HICCs can be distinguished: 1) amiloride-sensitive nonselective cat-ion channels (68, 390, 1079, 1080), at least some of which have been suggested to be related to ENaC, and which are in general insensitive to Gd 3ϩ and flufenamate (see Ref.…”

A Novel Inhibitor of Hypertonicity-Induced Cation Channels in HeLa Cells

“…Hypertonicity-induced cation channels (HICCs), for instance, have proven to be a most effective mechanism of Na + import in the regulatory volume increase (RVI) of a shrunken cell [3][4][5] and, also, to facilitate proliferation and significantly interfere with the initiation of apoptosis [6]. Despite the interesting role that HICCs appear to play in these processes, a detailed analysis of their interrelation is hindered by the very limited number of channel inhibitors available.…”

“…However, their concentration-response relations have not yet been obtained. Also, the latter is, unfortunately, known to quantitatively complex with several physiologically relevant anions, such as HCO 3 -, SO 4 2-and PO 4 2- [8], the omission of which will significantly reduce the amount of cell proliferation per se. In the present report, 2-aminoethoxydiphenyl borate (2-APB) is therefore introduced as a novel and efficient blocker of the HICC in HeLa cells, and its effects on channel activation as well as on the process of RVI are defined together and with reference to the established inhibitor flufenamic acid.…”