Function of spadin in neurological treatment of depression



Tandem P-domain weak inward rectifying K+ (TWIK)-related K+ channel 1 (TREK-1) and TWIK-related acid-sensitive K+ channel 3 (TASK-3) have been proposed to be related to depression. TREK-1 and TASK-3 antagonists are thought as the new potential treatments for depression. Spadin, a natural peptide released from the maturation of sortilin, which is also considered as the neurotensin receptor 3, works as the TREK-1 inhibitor to treat the depression. Spadin was known to be efficient, fast response and slight side-effect as the antidepressant.

Pharmacologic action

Spadin is an endogenous peptide derived from sortilin (a NTS3 receptor), selectively inhibiting TREK-1 channel, which is an effective treatment for depression. As a partial propeptide Ala12-Arg28, spadin associated with TREK-1 and sortilin complexes on the cell surface, moderating TREK-1 channel through endocytosis as well as lysosomal degradation. Spadin has the fast acting antidepression property with the activation of two specific markers. Spadin is regarded as the first blocker of TREK-1 channel, which is related to the depression and other neurological diseases.


Depression is known as a kind of neurological disorder, which was considered to be closely related to the two-pore domain potassium channel TREK-1. The antagonist of TREK-1 would be an effective antidepressant. Spadin, is a fast onset peptide antidepressant derived from maturation of sortilin receptor that specifically blocks TREK-1 channel. Spadin shows an effective affinity to inhibit the TREK-1 activity in hippocampal neurons in the experiment of many types of mice, demonstrating the specific antagonist ability of spadin on TREK-1 channel.

Pharmacokinetics and metabolism

Spadin is the first peptide antidepressant with fact acting nature. Spadin was first estimated through forced swimming test to be proved as an important antidepressant potential. The mice after spadin administration showed reduced floating and immobility times comparing with the controlled groups. The maximum value of reduced immobility times was at spadin-dose of 10-7 M in intracerebroventricular of 66.8%, 10-6 M in intravenous of 62.9% and 10-5 M in intraperitoneal of 55.30% administration. It is proposed that about 63% of arachidonic acid-stimulated TREK-1 current can be blocked by 100 nM of spadin. And IC50 value of 70.7 nM at 0 mV was also determined in the dose response experiment of spadin.


Borsotto M, Veyssiere J, Moha ou Maati H, Devader C, Mazella J, Heurteaux C. Targeting two-pore domain K+ channels TREK-1 and TASK-3 for the treatment of depression: a new therapeutic concept. British Journal of Pharmacology, 2015, 172, 771-784.

Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature, 2008, 455, 894-902.

Heurteaux C, Mazella J, Borsotto M. Spadin, a sortilin-derived peptide: a new concept in the antidepressant drug design. OCL, 2011, 18, 202-207.

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