This report was presented at The Journal of Physiology Symposium on Regulation of ion channels and transporters by phosphatidylinositol 4,5-bisphosphate (PIP2), Baltimore, MD, USA, 2 March 2007. It was commissioned by the Editorial Board and reflects the views of the author.
Regulation of M(Kv7.2/7.3) channels in neurons by PIP2 and products of PIP2 hydrolysis: significance for receptor-mediated inhibition
Article first published online: 21 JUL 2007
The Journal of Physiology
Volume 582, Issue 3, pages 917–925, August 2007
How to Cite
Brown, D. A., Hughes, S. A., Marsh, S. J. and Tinker, A. (2007), Regulation of M(Kv7.2/7.3) channels in neurons by PIP2 and products of PIP2 hydrolysis: significance for receptor-mediated inhibition. The Journal of Physiology, 582: 917–925. doi: 10.1113/jphysiol.2007.132498
- Issue published online: 21 JUL 2007
- Article first published online: 21 JUL 2007
- (Received 17 March 2007; accepted after revision 28 March 2007; first published online 29 March 2007)
M-channels are voltage-gated K+ channels that regulate the excitability of many neurons. They are composed of Kv7 (KCNQ) family subunits, usually Kv7.2 + Kv7.3. Native M-channels and expressed Kv7.2 + 7.3 channels are inhibited by stimulating Gq/11-coupled receptors – prototypically the M1 muscarinic acetylcholine receptor (M1-mAChR). The channels require membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to open and the effects of mAChR stimulation result primarily from the reduction in membrane PIP2 levels following Gq/phospholipase C-catalysed PIP2 hydrolysis. However, in sympathetic neurons, M-current inhibition by bradykinin appears to be mediated through the release and action of intracellular Ca2+ by inositol-1,4,5-trisphosphate (IP3), a product of PIP2 hydrolysis, rather than by PIP2 depletion. We have therefore compared the effects of bradykinin and oxotremorine-M (a muscarinic agonist) on membrane PIP2 in sympathetic neurons using a fluorescently tagged mutated C-domain of the PIP2 binding probe, ‘tubby’. In concentrations producing equal M-current inhibition, bradykinin produced about one-quarter of the reduction in PIP2 produced by oxotremorine-M, but equal reduction when PIP2 synthesis was blocked with wortmannin. Likewise, wortmannin restored bradykinin-induced M-current inhibition when Ca2+ release was prevented with thapsigargin. Thus, inhibition by bradykinin can use product (IP3/Ca2+)-dependent or substrate (PIP2) dependent mechanisms, depending on Ca2+ availability and PIP2 synthesis rates.