Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design

Mazella, Jean; Pétrault, Olivier; Lucas, George L.; Deval, Emmanuel; Béraud-Dufour, Sophie; Gandin, Carine; Yacoubi, Malika El; Widmann, Catherine; Guyon, Alice; Chevet, Éric; Taouji, Saı̈d; Conductier, Grégory; Corinus, Alain; Coppola, Thierry; Gobbi, Gabriella; Nahon, Jean‐Louis; Heurteaux, Catherine; Borsotto, Marc

doi:10.1371/journal.pbio.1000355

Cited by 153 publications

(232 citation statements)

References 51 publications

(100 reference statements)

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“…In contrast, TREK-1 and TREK-2 chan-nels are regulated differently by extracellular (EC) 2 acidification; TREK-1 is inhibited, and TREK-2 is activated (16,17). TREK-1 is inhibited by the sortilin-derived neuropeptide spadin, and TREK-2 is insensitive to spadin (18,19). Recently, we described the differential pharmacological effect of the polycationic dye ruthenium red (RR) on TREK channels; TREK-2 is potently inhibited by the dye, whereas TREK-1 is insensitive to RR (20).…”

mentioning

confidence: 99%

Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits

Lengyel

Czirják

Enyedi

2016

Journal of Biological Chemistry

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mentioning

confidence: 99%

Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits

Lengyel

Czirják

Enyedi

2016

Journal of Biological Chemistry

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“…TREK1 knockout mice (TREK1 −/− ) display a depression-resistant phenotype (18). Recently, it was reported that spadin, a sortilin-derived peptide, targets TREK1 to generate an antidepressive effect (35). In addition, fluoxetine, the chemical name of the widely used antidepressant Prozac, has been shown to inhibit TREK1 at clinical concentrations (15).…”

Section: Discussionmentioning

confidence: 99%

“…TREK1 has been implicated in depression (18,34,35) and has been proposed to be a therapeutic target of the antidepressant fluoxetine, which has been shown to inhibit channel activity (15). The E306A mutation was found to have reduced fluoxetine inhibition (15), suggesting a possible involvement of the TREK1 C terminus.…”

Section: Fluoxetine Inhibition Of Trek1 Channel Activity By Membranementioning

confidence: 99%

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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“…L'autre consiste à modifier des protéines natives avec des molé-cules chimiques synthétiques sensibles cible dans le traitement de la dépres-sion [7]. En accord avec cette hypothèse, la spadine, un peptide dérivé de la sortiline qui inhibe TREK1, a un effet antidépresseur [8]. Chez l'homme, une étude a également rapporté un rôle de TREK1 dans la régulation de l'humeur et dans la résistance au traitement antidépresseur.…”

Section: Les Canaux Potassique à Deux Domaines Poresunclassified

Télécommander l’activité des canaux ioniques endogènes par la lumière

Sandoz

Isacoff

2012

Med Sci (Paris)

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Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design

Abstract: We found that spadin, a natural peptide derived from sortilin, blocks the mouse TREK-1 channel and might be an efficient and fast-acting antidepressant.

Cited by 153 publications

References 51 publications

Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits

Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits

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

Télécommander l’activité des canaux ioniques endogènes par la lumière

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