Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.
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.
Mazella
Jean
J
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, Valbonne, France.
Pétrault
Olivier
O
Lucas
Guillaume
G
Deval
Emmanuel
E
Béraud-Dufour
Sophie
S
Gandin
Carine
C
El-Yacoubi
Malika
M
Widmann
Catherine
C
Guyon
Alice
A
Chevet
Eric
E
Taouji
Said
S
Conductier
Grégory
G
Corinus
Alain
A
Coppola
Thierry
T
Gobbi
Gabriella
G
Nahon
Jean-Louis
JL
Heurteaux
Catherine
C
Borsotto
Marc
M
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
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
Curr Pharm Des. 2005;11(2):145-55
15638755
Neuron. 2002 Mar 28;34(1):13-25
11931738
Neuropsychopharmacology. 2008 Nov;33(12):2810-9
18288090
Nature. 2004 Feb 26;427(6977):843-8
14985763
Nature. 2008 Oct 16;455(7215):894-902
18923511
Expert Rev Neurother. 2008 Jan;8(1):1-3
18088195
Arch Gen Psychiatry. 2005 Jun;62(6):593-602
15939837
J Neurosci. 2003 Feb 15;23(4):1198-205
12598608
Trends Neurosci. 2005 Aug;28(8):436-45
15982754
J Biol Chem. 1990 Jul 25;265(21):12434-43
2165064
EMBO J. 2000 Jun 1;19(11):2483-91
10835347
Mol Cell Proteomics. 2005 Jul;4(7):936-44
15814614
EMBO J. 1999 Feb 1;18(3):595-604
9927419
EMBO J. 2006 Dec 13;25(24):5864-72
17110924
EMBO J. 1998 Aug 3;17(15):4283-90
9687497
EMBO J. 2001 May 1;20(9):2180-90
11331584
EMBO J. 1997 Sep 1;16(17):5464-71
9312005
J Neurosci. 2000 Jun 1;20(11):4030-6
10818138
EMBO J. 2003 Oct 15;22(20):5403-11
14532113
J Affect Disord. 2001 Jan;62(1-2):77-91
11172875
EMBO J. 2003 Dec 15;22(24):6430-7
14657016
Nat Neurosci. 2006 Sep;9(9):1134-41
16906152
J Neuroimmunol. 1994 Sep;53(2):173-80
8071431
Behav Pharmacol. 1997 Nov;8(6-7):477-96; discussion 497-504
9832964
J Neurosci. 1998 Dec 1;18(23):10150-6
9822768
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3908-13
8632988
Curr Genomics. 2009 Apr;10(2):93-101
19794881
Nature. 1977 Apr 21;266(5604):730-2
559941
Trends Pharmacol Sci. 1999 Feb;20(2):59-61
10101965
J Neurosci. 1995 Nov;15(11):7539-47
7472505
J Biomol Screen. 2007 Oct;12(7):946-55
17942787
J Neurosci. 1996 Apr 1;16(7):2365-72
8601816
Pharmacol Biochem Behav. 2000 Aug;66(4):811-7
10973520
Psychopharmacology (Berl). 1985;85(3):367-70
3923523
Cell Mol Life Sci. 2009 Aug;66(16):2677-89
19434368
J Biol Chem. 1998 Oct 9;273(41):26273-6
9756851
J Biol Chem. 2004 Nov 26;279(48):50221-9
15364913
J Clin Psychiatry. 2001;62 Suppl 4:7-11; discussion 37-40
11229789
Eur J Neurosci. 2002 Sep;16(5):817-22
12372017
Nat Neurosci. 2006 Sep;9(9):1081-3
16936765
J Neurosci. 2005 Jun 29;25(26):6156-66
15987945
Neuropharmacology. 1985 Apr;24(4):285-90
4039801
Nat Rev Drug Discov. 2005 Sep;4(9):775-90
16138108
Eur J Neurosci. 2005 Jan;21(1):1-14
15654838
Neuroscience. 2001;103(4):899-919
11301200
J Comp Neurol. 2003 Jul 7;461(4):483-505
12746864
Psychopharmacology (Berl). 2005 Nov;182(3):335-44
16001105
Science. 2003 Aug 8;301(5634):805-9
12907793
J Neurosci. 2008 Aug 20;28(34):8545-52
18716213
Am J Physiol Renal Physiol. 2000 Nov;279(5):F793-801
11053038
Biochem Biophys Res Commun. 1984 May 16;120(3):812-9
6329185
Neuropsychopharmacology. 1999 Aug;21(2 Suppl):91S-98S
10432494