title: Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.
abstract: Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative antidepressant of new generation with a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Mazella
authors.forename: Olivier
authors.initials: O
authors.lastname: Pétrault
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lucas
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Deval
authors.forename: Sophie
authors.initials: S
authors.lastname: Béraud-Dufour
authors.forename: Carine
authors.initials: C
authors.lastname: Gandin
authors.forename: Malika
authors.initials: M
authors.lastname: El-Yacoubi
authors.forename: Catherine
authors.initials: C
authors.lastname: Widmann
authors.forename: Alice
authors.initials: A
authors.lastname: Guyon
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.forename: Said
authors.initials: S
authors.lastname: Taouji
authors.forename: Grégory
authors.initials: G
authors.lastname: Conductier
authors.forename: Alain
authors.initials: A
authors.lastname: Corinus
authors.forename: Thierry
authors.initials: T
authors.lastname: Coppola
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gobbi
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Nahon
authors.forename: Catherine
authors.initials: C
authors.lastname: Heurteaux
authors.forename: Marc
authors.initials: M
authors.lastname: Borsotto
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D019556:COS Cells; D002522:Chlorocebus aethiops; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011903:Raphe Nuclei / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000928:Antidepressive Agents; D017362:Cyclic AMP Response Element-Binding Protein; D010455:Peptides; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D012701:Serotonin; D000099183:Sortilin; C103742:potassium channel protein TREK-1; C551795:spadin peptide
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