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PMID: 21540350 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Probing the regulation of TASK potassium channels by PI4,5P₂ with switchable phosphoinositide phosphatases.

The Journal of physiology ·Vol. 589 ·No. Pt 13 ·2011-07-01 ·Pages 3149-62

Lindner M, Leitner MG, Halaszovich CR, Hammond GR, Oliver D

Abstract

TASK channels are background K+ channels that contribute to the resting conductance in many neurons. A key feature of TASK channels is the reversible inhibition by Gq-coupled receptors, thereby mediating the dynamic regulation of neuronal activity by modulatory transmitters. The mechanism that mediates channel inhibition is not fully understood. While it is clear that activation of Gαq is required, the immediate signal for channel closure remains controversial. Experimental evidence pointed to either phospholipase C (PLC)-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) as the cause for channel closure or to a direct inhibitory interaction of active Gαq with the channel. Here, we address the role of PI(4,5)P2 for G-protein-coupled receptor (GPCR)-mediated TASK inhibition by using recently developed genetically encoded tools to alter phosphoinositide (PI) concentrations in the living cell.When expressed in CHO cells, TASK-1- and TASK-3-mediated currents were not affected by depletion of plasma membrane PI(4,5)P2 either via the voltage-activated phosphatase Ci-VSP or via chemically triggered recruitment of a PI(4,5)P2-5'-phosphatase. Depletion of both PI(4,5)P2 and PI(4)P via membrane recruitment of a novel engineered dual-specificity phosphatase also did not inhibit TASK currents. In contrast, each of these methods produced robust inhibition of the bona fide PI(4,5)P2-dependent channel KCNQ4. Efficient depletion of PI(4,5)P2 and PI(4)P was further confirmed with a fluorescent phosphoinositide sensor. Moreover, TASK channels recovered normally from inhibition by co-expressed muscarinic M1 receptors when resynthesis of PI(4,5)P2 was prevented by depletion of cellular ATP. These results demonstrate that TASK channel activity is independent of phosphoinositide concentrations within the physiological range. Consequently, Gq-mediated inhibition of TASK channels is not mediated by depletion of PI(4,5)P2.

MeSH Terms
Adenosine Triphosphate/deficiency Amino Acid Sequence Animals CHO Cells Cricetinae Cricetulus Genes, Switch Humans Molecular Sequence Data Nerve Tissue Proteins/antagonists & inhibitors,physiology Phosphatidylinositol 4,5-Diphosphate/antagonists & inhibitors,physiology Phosphoric Monoester Hydrolases/antagonists & inhibitors,physiology Potassium Channels, Tandem Pore Domain/antagonists & inhibitors,physiology Receptors, G-Protein-Coupled/physiology
Chemicals
KCNK9 protein, human Nerve Tissue Proteins Phosphatidylinositol 4,5-Diphosphate Potassium Channels, Tandem Pore Domain Receptors, G-Protein-Coupled potassium channel subfamily K member 3 Adenosine Triphosphate polyphosphoinositide phosphatase Phosphoric Monoester Hydrolases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lindner Moritz
Institute of Physiology and Pathophysiology, Department of Neurophysiology, Philipps University, Deutschhausstrasse 1-2, 35037 Marburg, Germany.
Leitner Michael G
Halaszovich Christian R
Hammond Gerald R V
Oliver Dominik
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Article Info
Journal
The Journal of physiology
Abbr.
J Physiol
ISSN
1469-7793
DOI
10.1113/jphysiol.2011.208983
Published
2011-07-01
Epub
2011-00-03
Pages
3149-62
Language
English
Region
England
NLM ID
0266262
PMCID
PMC3145931
Subset
IM
External Links
PubMed source DOI: 10.1113/jphysiol.2011.208983 PMC Full Text View journal details
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