AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K(+) channels into open leak channels.
TREK channels are unique among two-pore-domain K(+) channels. They are activated by polyunsaturated fatty acids (PUFAs) including arachidonic acid (AA), phospholipids, mechanical stretch and intracellular acidification. They are inhibited by neurotransmitters and hormones. TREK-1 knockout mice have impaired PUFA-mediated neuroprotection to ischemia, reduced sensitivity to volatile anesthetics and altered perception of pain. Here, we show that the A-kinase-anchoring protein AKAP150 is a constituent of native TREK-1 channels. Its binding to a key regulatory domain of TREK-1 transforms low-activity outwardly rectifying currents into robust leak conductances insensitive to AA, stretch and acidification. Inhibition of the TREK-1/AKAP150 complex by Gs-coupled receptors such as serotonin 5HT4sR and noradrenaline beta2AR is as extensive as for TREK-1 alone, but is faster. Inhibition of TREK-1/AKAP150 by Gq-coupled receptors such as serotonin 5HT2bR and glutamate mGluR5 is much reduced when compared to TREK-1 alone. The association of AKAP150 with TREK channels integrates them into a postsynaptic scaffold where both G-protein-coupled membrane receptors (as demonstrated here for beta2AR) and TREK-1 dock simultaneously.
Sandoz
Guillaume
G
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR6097, Institut Paul Hamel, 660 route des lucioles, 06560 Valbonne, France.
Thümmler
Susanne
S
Duprat
Fabrice
F
Feliciangeli
Sylvain
S
Vinh
Joëlle
J
Escoubas
Pierre
P
Guy
Nicolas
N
Lazdunski
Michel
M
Lesage
Florian
F
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004285:Dogs; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009865:Oocytes; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D040901:Proteomics; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D014981:Xenopus
D048868:Adaptor Proteins, Signal Transducing; D024683:Potassium Channels, Tandem Pore Domain; D018343:Receptors, Adrenergic, beta-2; D011956:Receptors, Cell Surface; C103742:potassium channel protein TREK-1; D016718:Arachidonic Acid; D043802:GTP-Binding Protein alpha Subunits, Gq-G11