| 19840997 |
Kreneisz O, Benoit JP, Bayliss DA, Mulkey DK: AMP-activated protein kinase inhibits TREK channels. J Physiol. 2009 Dec 15;587(Pt 24):5819-30. Epub .
AMP-activated protein kinase (AMPK) is a serine/threonine kinase activated by conditions that increase the AMP : ATP ratio. In carotid body glomus cells, AMPK is thought to link changes in arterial O (2) with activation of glomus cells by inhibition of unidentified background K (+) channels. Modulation by AMPK of individual background K (+) channels has not been described. Here, we characterize effects of activated AMPK on recombinant TASK-1, TASK-3, TREK-1 and TREK-2 background K (+) channels expressed in HEK293 cells. We found that TREK-1 and TREK-2 channels but not TASK-1 or TASK-3 channels are inhibited by AMPK. AMPK-mediated inhibition of TREK involves key serine residues in the C-terminus that are also known to be important for PKA and PKC channel modulation; inhibition of TREK-1 requires Ser-300 and Ser-333 and inhibition of TREK-2 requires Ser-326 and Ser-359. Metabolic inhibition by sodium azide can also inhibit both TREK and TASK channels. The effects of azide on TREK occlude subsequent channel inhibition by AMPK and are attenuated by expression of a dominant negative catalytic subunit of AMPK (dnAMPK), suggesting that metabolic stress modulates TREK channels by an AMPK mechanism. By contrast, inhibition of TASK channels by azide was unaffected by expression of dnAMPK, suggesting an AMPK-independent mechanism. In addition, prolonged exposure (6-7 min) to hypoxia ( = 11 +/- 1 mmHg) inhibits TREK channels and this response was blocked by expression of dnAMPK. Our results identify a novel modulation of TREK channels by AMPK and indicate that select residues in the C-terminus of TREK are points of convergence for multiple signalling cascades including AMPK, PKA and PKC. To the extent that carotid body O (2) sensitivity is dependent on AMPK, our finding that TREK-1 and TREK-2 channels are inhibited by AMPK suggests that TREK channels may represent the AMPK-inhibited background K (+) channels that mediate activation of glomus cells by hypoxia. |
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