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First published on March 20, 2007; DOI: 10.1124/mol.106.033241

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Received for publication December 7, 2006.
Revised March 19, 2007.
Accepted for publication March 20, 2007.

G{alpha}q MEDIATED REGULATION OF TASK3 TWO PORE DOMAIN POTASSIUM CHANNELS: THE ROLE OF PROTEIN KINASE C

Emma L Veale 1, Louise Kennard 1, Gemma L Sutton 1, Georgina MacKenzie 1, Cristina Sandu 2, Alistair Mathie 1*

1 Imperial College London 2 University of Heidelberg

* Address correspondence to: E-mail: a.mathie{at}imperial.ac.uk

Abstract

The TASK subfamily of two pore domain potassium channels (K2P) gives rise to leak K currents which contribute to the resting membrane potential of many neurons and regulate their excitability. K2P channels are highly regulated by phosphorylation and by G protein mediated pathways. In this study, we show that protein kinase C (PKC) inhibits recombinant TASK3 channels. Inhibition by PKC is blocked by the PKC inhibitors BIM and Go 6976. Gene silencing experiments with a validated siRNA sequence against PKC{alpha} ablates the effect of PKC. PKC acts directly on hTASK3 channels to phosphorylate an identified amino acid in the C terminus region (T341), thereby reducing channel current. PKC also inhibits mTASK3 channels despite them having a quite different C terminus structure to hTASK3 channels. Activation of M3 muscarinic receptors inhibits both hTASK3 channels expressed in tsA-201 cells and IKSO in mouse cerebellar granule neurons through the activation of the G protein G{alpha}q since both effects are abolished by the selective G{alpha}q antagonist, YM-254890. This inhibition is not directly transduced through activation of PKC since inhibition persists in mutated PKC-insensitive hTASK3 channels. Instead, inhibition seems to occur through a direct action of G{alpha}q on the channel. Nevertheless, pre-activation of PKC blocks muscarinic inhibition of both TASK3 channels and IKSO. Our results suggest that activation of PKC (via phospholipase C) has a role in opposing inhibition following M3 receptor activation rather than transducing it and may act as a negative regulator of G protein modulation to prevent prolonged current inhibition.


Key words: Muscarinic cholinergic, Ion channel regulation, Potassium, Gq/11 family, Protein Kinase C, Func. analysis receptor/ion channel mutants


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