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Regulation of M(Kv7.2/7.3) channels in neurons by PIP2 and products Of PIP2 hydrolysis: significance for receptor-mediated inhibition

Brown, DA; Hughes, SA; Marsh, SJ; 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. JOURNAL OF PHYSIOLOGY-LONDON , 582 (3) 917 - 925. 10.1113/jphysiol.2007.132498. Gold open access

Abstract

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 G(q/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 G(q)/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.

Type: Article
Title: Regulation of M(Kv7.2/7.3) channels in neurons by PIP2 and products Of PIP2 hydrolysis: significance for receptor-mediated inhibition
Location: Baltimore, MD
Open access status: An open access publication
DOI: 10.1113/jphysiol.2007.132498
Publisher version: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC20752...
Keywords: RAT SYMPATHETIC NEURONS, POTASSIUM M-CHANNELS, PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE, KCNQ CHANNELS, MUSCARINIC SUPPRESSION, SIGNALING MICRODOMAINS, PHOSPHOLIPASE-C, LIVING CELLS, ION CHANNELS, K+ CHANNELS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/132083
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