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Trendsetters
Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.
Heinz Valtin
Editor, TRENDSETTERS
Certain ion channels, including so-called CIC-2 Cl– channels and TREK-1 K+ channels (1,2), are activated by low concentrations of arachidonic acid and other unsaturated fatty acids. Perhaps not surprisingly—since nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the degradation of arachidonic acid—it has now been shown that NSAIDs themselves can increase the activity of CIC-2 (and by extension, presumably of other ion channels as well) (2). These results suggest that ion channels may be involved in the mode of action of NSAIDs. This précis deals with recent data that bear on that possibility.
First, data on the TREK-1 K+ channel. This channel is a two-transmembrane-domain, two-pore K+ channel, which is widely distributed among epithelial and nonepithelial tissues. TREK-1 is inhibited by PKA (protein kinase A) and by reduction of external pH, and it is activated by mechanical stretch, internal pH, volatile anesthetics, and fatty acids. Activation occurs through release from tonic inhibition of the channel, and in the case of fatty acids (including the unsaturated oleic and eladic acids but not the saturated palmitic acid) this action utilizes a clearly defined region of the channel, namely the intracellular COOH-terminal portion (1).
Like TREK-1, CIC-2 Cl– channels are widely expressed in epithelial and nonepithelial tissues. Human CIC-2 is activated by the same panel of unsaturated fatty acids listed for the K+ channel, although in contrast to TREK-1, CIC-2 is activated (not inhibited) by PKA (2). The COOH terminus of CIC-2 contains several potential sites for phosphorylation, and it is therefore tempting to speculate that this is the same defined region through which unsaturated fatty acids activate the K+ channel—that is, that the two channels share a common mechanism for modulation. Together, these findings on TREK-1 K+ channels and CIC-2 Cl– channels extend and confirm previous suggestions in the literature that binding of arachidonic acid to ion channels may serve as a physiological messenger in the regulation of such channels.
If this suggestion is indeed correct, then we need to know all we can about arachidonic acid metabolism; yet many gaps in our understanding of this area remain. In particular, little is known about the production of arachidonic acid by the various isoforms of secretory phospholipase A2 and their receptors in physiological and pathological conditions. It is known that the two cyclooxygenase isoforms COX-1 and COX-2 use arachidonic acid produced by phospholipase A2 to generate prostaglandins and that the prostaglandins protect the integrity of renal and gastrointestinal tissues. For example, inhibition of COX-1 by NSAIDs can seriously damage such tissues (3), and these highly undesirable side effects can also occur when specific inhibitors of COX-2 are applied therapeutically to relieve pain, inflammation, and fever (3). It is possible that indirect rather than direct effects of NSAIDs produce the side effects (3)—perhaps, for example, through the action of NSAID-stimulated arachidonic acid on ion channels in epithelia, in platelets, and in blood vessels.
The widespread use of NSAIDs, our inadequate understanding of the side effects of NSAIDs (3), and still unresolved problems with the therapeutic actions of NSAIDs (3) warrant further studies to elucidate arachidonic acid metabolism, the direct effects of this acid on ion channels, and the indirect effects of NSAIDs on the channels.
| Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only.
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References
| Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only. |
This article has been cited by other articles:
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  J. Cuppoletti, K. P. Tewari, A. M. Sherry, E. Y. Kupert, and D. H. Malinowska ClC-2 Cl{-} channels in human lung epithelia: activation by arachidonic acid, amidation, and acid-activated omeprazole Am J Physiol Cell Physiol, July 1, 2001; 281(1): C46 - C54. [Abstract] [Full Text] [PDF]
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R. T. Worrell, H.-F. Bao, D. D. Denson, and D. C. Eaton Contrasting effects of cPLA2 on epithelial Na+ transport Am J Physiol Cell Physiol, July 1, 2001; 281(1): C147 - C156. [Abstract] [Full Text] [PDF]
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