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PIP2-dependent inhibition of M-type (Kv7.2/7.3) potassium channels: direct on-line assessment of PIP2 depletion by Gq-coupled receptors in single living neurons

Hughes, S; Marsh, SJ; Tinker, A; Brown, DA; (2007) PIP2-dependent inhibition of M-type (Kv7.2/7.3) potassium channels: direct on-line assessment of PIP2 depletion by Gq-coupled receptors in single living neurons. PFLUG ARCH EUR J PHY , 455 (1) 115 - 124. 10.1007/s00424-007-0259-6.

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Abstract

The open state of M(Kv7.2/7.3) potassium channels is maintained by membrane phosphatidylinositol-4,5-bisphosphate (PI(4,5)P-2). They can be closed on stimulating receptors that induce PI(4,5)P-2 hydrolysis. In sympathetic neurons, closure induced by stimulating M1-muscarinic acetylcholine receptors (mAChRs) has been attributed to depletion of PI(4,5)P-2, whereas closure by bradykinin B-2-receptors (B2-BKRs) appears to result from formation of IP3 and release of Ca2+, implying that BKR stimulation does not deplete PI(4,5)P-2. We have used a fluorescently tagged PI(4,5)P-2-binding construct, the C-domain of the protein tubby, mutated to increase sensitivity to PI(4,5)P-2 changes (tubby-R332H-cYFP), to provide an on-line read-out of PI(4,5)P-2 changes in single living sympathetic neurons after receptor stimulation. We find that the mAChR agonist, oxotremorine-M (oxo-M), produces a near-complete translocation of tubby-R332H-cYFP into the cytoplasm, whereas bradykinin (BK) produced about one third as much translocation. However, translocation by BK was increased to equal that produced by oxo-M when synthesis of PI(4,5)P-2 was inhibited by wortmannin. Further, wortmannin 'rescued' M-current inhibition by BK after Ca2+ -dependent inhibition was reduced by thapsigargin. These results provide the first direct support for the view that BK accelerates PI(4,5)P-2 synthesis in these neurons, and show that the mechanism of BKR-induced inhibition can be switched from Ca2+ dependent to PI(4,5)P-2 dependent when PI(4,5)P-2 synthesis is inhibited.

Type: Article
Title: PIP2-dependent inhibition of M-type (Kv7.2/7.3) potassium channels: direct on-line assessment of PIP2 depletion by Gq-coupled receptors in single living neurons
DOI: 10.1007/s00424-007-0259-6
Keywords: phosphatidylinositol-4,5-bisphosphate, tubby, phospholipase-C delta-PH, muscarinic receptors, bradykinin, M-current, sympathetic neuron, RAT SYMPATHETIC NEURONS, PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE, MUSCARINIC SUPPRESSION, MEDIATED INHIBITION, PHOSPHOLIPASE-C, ION CHANNELS, K+ CHANNEL, CALCIUM, MODULATION, GANGLION
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/132082
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