Specificity of activation by phosphoinositides determines lipid regulation of Kir channels

Rohács, Tibor; Lopes, Coeli M.; Jin, Taihao; Ramdya, Pavan; Molnár, Zoltán; Logothetis, Diomedes E.

doi:10.1073/pnas.0236364100

Cited by 196 publications

(243 citation statements)

References 37 publications

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“…These results suggest that anchoring of the C terminus to the membrane occurs via a nonspecific electrostatic interaction to phosphoinositide (36) of the post-M4 polybasic motif and not to specific binding of PI(4,5)P2. Such nonspecific binding is reminiscent of the MARKS effector domain (33) and GIRK and K ATP channels (37,38) and differs from the stereo-specific PI(4,5)P2-selective interaction of the IRK1 channel and of the plextrin homology domain of PLC (36). Such nonspecific charge interaction is consistent with TREK1 channel regulation by anionic phospholipids in the inner leaflet lipid and not by cationic lipids (8).…”

Section: Discussionsupporting

confidence: 53%

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

Sandoz

Bell

Isacoff

2011

Proc. Natl. Acad. Sci. U.S.A.

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TREK channels produce background currents that regulate cell excitability. These channels are sensitive to a wide variety of stimuli including polyunsaturated fatty acids (PUFAs), phospholipids, mechanical stretch, and intracellular acidification. They are inhibited by neurotransmitters, hormones, and pharmacological agents such as the antidepressant fluoxetine. TREK1 knockout mice have impaired PUFA-mediated neuroprotection to ischemia, reduced sensitivity to volatile anesthetics, altered perception of pain, and a depression-resistant phenotype. Here, we investigate TREK1 regulation by Gq-coupled receptors (GqPCR) and phospholipids. Several reports indicate that the C-terminal domain of TREK1 is a key regulatory domain. We developed a fluorescent-based technique that monitors the plasma membrane association of the C terminus of TREK1 in real time. Our fluorescence and functional experiments link the modulation of TREK1 channel function by internal pH, phospholipid, and GqPCRs to TREK1-C-terminal domain association to the plasma membrane, where increased association results in greater activity. In keeping with this relation, inhibition of TREK1 current by fluoxetine is found to be accompanied by dissociation of the C-terminal domain from the membrane.T REK1 is a two-pore-domain K + (K 2P ) channel that produces a nearly time-and voltage-independent background current. This current drives the membrane potential toward the K + equilibrium potential and thus affects input resistance. 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). These mice also display a depression-resistant phenotype (18). This phenotype is in agreement with the sensitivity of TREK1 to fluoxetine, a widely used antidepressant drug.In the last decade, much effort has been made to elucidate the gating mechanism of the TREK1 channel. The cytosolic carboxylterminal domain of TREK1 that follows its fourth transmembrane domain (post-M4) has been implicated in its function and regulation. A glutamate residue, E306, has been shown to be a key element for stimulation by intracellular acidification (19) and a cluster of basic residues in the same region has been shown to be involved in TREK1 regulation by phospholipid (8). However, the mechanism of regulation of the channel by Gq-coupled receptors (GqPCR) and by pharmacological agents such as fluoxetine remains unclear.I...

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Section: Discussionsupporting

confidence: 53%

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

Sandoz

Bell

Isacoff

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Many members of the Kir (inwardly-rectifying K ϩ channel) family of K ϩ channels are regulated by G protein-coupled receptors that alter the P o over short time frames through phosphatidylinositol bisphosphate metabolism or protein-protein interactions (18,19). We found that co-expression of the CaR WT and Kir4.1 in Xenopus oocytes led to reduced whole cell currents, whereas the nonfunctional mutant CaR R795W had no effect (10).…”

Section: Control Of Kir41 Cell Surface Abundance By Car-mentioning

confidence: 77%

“…These results indicate that the effects of the CaR on Kir4.1 are distinct from the conventional effects of G␣ q -coupled receptors that involve short term regulation of second messengers such as inositol 1,4,5-trisphosphate or phosphatidylinositol bisphosphate, kinases such as PKC, or protein-protein interactions that occur over seconds. Instead, they depend on protein trafficking that occurs over a time scale of a few to many minutes (10,19).…”

Section: Discussionmentioning

confidence: 99%

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Kuy

Huang

Ding³

et al. 2011

Journal of Biological Chemistry

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The Ca 2؉ -sensing receptor (CaR) regulates salt and water transport in the kidney as demonstrated by the association of gain of function CaR mutations with a Bartter syndrome-like, salt-wasting phenotype, but the precise mechanism for this effect is not fully established. We found previously that the CaR interacts with and inactivates an inwardly rectifying K ؉ channel, Kir4.1, which is expressed in the distal nephron that contributes to the basolateral K ؉ conductance, and in which loss of function mutations are associated with a complex phenotype that includes renal salt wasting. We now find that CaR inactivates Kir4.1 by reducing its cell surface expression. Mutant CaRs reduced Kir4.1 cell surface expression and current density in HEK-293 cells in proportion to their signaling activity. Mutant, activated G␣ q reduced cell surface expression and current density of Kir4.1, and these effects were blocked by RGS4, a protein that blocks signaling via G␣ i and G␣ q . Other ␣ subunits had insignificant effects. Knockdown of caveolin-1 blocked the effect of G␣ q on Kir4.1, whereas knockdown of the clathrin heavy chain had no effect. CaR had no comparable effect on the renal outer medullary K ؉ channel, an apical membrane distal nephron K ؉ channel that is internalized by clathrin-coated vesicles. Co-immunoprecipitation studies showed that the CaR and Kir4.1 physically associate with caveolin-1 in HEK cells and in kidney extracts. Thus, the CaR decreases cell surface expression of Kir4.1 channels via a mechanism that involves G␣ q and caveolin. These results provide a novel molecular basis for the inhibition of renal NaCl transport by the CaR.Sodium transport in the distal nephron determines body volume and blood pressure as demonstrated by the fact that mutations in genes expressed in this region of the kidney can cause either salt retention and high blood pressure or salt wasting and low blood pressure (1). A number of genetically distinct syndromes caused by abnormalities of transport proteins expressed in the distal nephron lead to phenotypes characterized by salt wasting. Bartter syndrome can result from loss of function mutations of the NaK 2 Cl co-transporter (NKCC2), 2 the renal outer medullary K ϩ channel (ROMK or Kir1.1), or the ClC-Kb (basolateral Cl Ϫ channel). A variant also characterized by sensorineural deafness is caused by loss of function mutations in an accessory protein for ClC-Kb, barttin (Bartter syndrome neuraosensory deafness or BSND) (1-5). The hypocalciuric, hypomagnesemic variant of Bartter syndrome, Gitelman syndrome, is due to loss of function mutations of the thiazide-sensitive NaCl co-transporter (6). The recently described SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) or EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy) syndrome is caused by loss of function mutations in Kir4.1 (KCNJ10), an inwardly rectifying K ϩ channel that is expressed in the basolateral membrane of the distal nephron (7-10). Presumably, reduced acti...

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“…In particular, PIP 2 directly modulates the activity of ion channels and transporters ( Hilgemann and Ball, 1996 ;Fan and Makielski, 1997 ;Runnels et al, 2002 ;Roh á cs et al, 2003 ;Chemin et al, 2005 ;Suh and Hille 2005 ;Brauchi et al, 2007 ;Hilgemann, 2007 ;Roh á cs 2007 ;Voets and Nilius, 2007 ). In spite of the key roles of PIP 2 and BK channels in cell excitability and signaling, it remains unknown whether PIP 2 can directly modulate BK channel function.…”

Section: Excised Patch Recordings From Vascular Myocytesmentioning

confidence: 99%

Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway

Vaithianathan¹,

Bukiya²,

Liu³

et al. 2008

J Cell Biol

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Specificity of activation by phosphoinositides determines lipid regulation of Kir channels

Cited by 196 publications

References 37 publications

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

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

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway

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