AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K+ channels into open leak channels

Abstract

TREK channels are unique among two-pore-domain K þ 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 b2AR 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 b2AR) and TREK-1 dock simultaneously.

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

“…Previous studies have described an interaction between Popeye domain‐containing proteins (Popdc1 and Popdc2) and TREK‐1 that is important for its regulation by protein kinase A, with implications for pacemaking in the mouse 7. Similarly, even earlier work identified an association between TREK‐1 and A kinase anchor protein 150 that controls response of channel to Gs‐coupled receptor activation 42. Our new findings together with our previous work8 indicate that β IV ‐spectrin associates with TREK‐1 and is essential for its proper membrane targeting in myocytes throughout the heart.…”

Mtap2 Is a Constituent of the Protein Network That Regulates Twik-Related K+Channel Expression and Trafficking

“…Mtap2c-mut was produced by PCR. Plasmids for expression of AKAP150, TREK-1, and the truncated mutants of TREK-1 have been described previously (Patel et al, 1998;Sandoz et al, 2006).…”

“…A-kinase anchoring protein 150 (AKAP150) is a constituent of native TREK-1 channels in the brain (Sandoz et al, 2006). AKAP150 interacts with the post-M4 region of TREK-1 that is necessary for activation by PUFAs, phospholipids, stretch and intracellular acidification, and for regulation by neurotransmitters and hormones.…”

Optical probing of a dynamic membrane interaction that regulates the TREK1 channel

“…Having observed a correlation between C-terminus membrane interaction and channel activity, we asked whether modulation of the former could underlie the known modulation of TREK1 channel activity by GqPCRs (8,12). As observed earlier for GqPCRs, we found that activation of either the serotonin 5HT2c receptor (5HT2cR) or of the group I metabotropic glutamate receptor, mGluR1a, inhibits TREK1 current (Fig.…”

“…TREK1 displays low basal activity when expressed alone (1) but can be strongly stimulated by temperature (2), mechanical stretch (3), external alkalization (4), intracellular acidification (5), polyunsaturated fatty acids (PUFAs) (6), lysophospholipids (7), phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] (8, 9), and pharmacological agents such as volatile anesthetics (10) and riluzole (11). TREK1 is inhibited by neurotransmitters and hormones that activate Gq and Gs pathways (3,(12)(13)(14) and pharmacological agents such as the antidepressant drug fluoxetine (15). TREK1 gene inactivation produces mice with decreased sensitivity to volatile anesthetics, impaired PUFA-mediated neuroprotection (16), and altered perception of pain (17).…”