Targeting two‐pore domain K⁺ channels TREK‐1 and TASK‐3 for the treatment of depression: a new therapeutic concept

Abstract

Depression is a disease that is particularly frequent, affecting up to 20% of the population in Western countries. The origins of this pathology involve multiple genes as well as environmental and developmental factors leading to a disorder that remains difficult to treat. Several therapies for depression have been developed and these mainly target monoamine neurotransmitters. However, these treatments are not only associated with numerous adverse effects, but they are also ineffective for more than one-third of patients. Therefore, the need to develop new concepts to treat depression is crucial. Recently, studies using knockout mouse models have provided evidence for a crucial role of two members of the two-pore domain potassium channel (K2P) family, tandem P-domain weak inward rectifying K + (TWIK)-related K + channel 1 (TREK-1) and TWIK-related acid-sensitive K + channel 3 (TASK-3) in the pathophysiology of depression. It is believed that TREK-1 and TASK-3 antagonists could lead to the development of new antidepressants. Herein, we describe the discovery of spadin, a natural peptide released from the maturation of the neurotensin receptor-3 (also known as sortilin), which specifically blocks the activity of the TREK-1 channel and displays particular antidepressant properties, with a rapid onset of action and the absence of adverse effects. The development of such molecules may open a new era in the field of psychiatry. AbbreviationsBDNF, brain-derived neurotrophic factor; COP, coatomer protein; FST, forced swimming test; K2P, two-pore domain potassium channel; MDD, major depressive disorder; NSC, neural stem cell; NSF, novelty-suppressed feeding task; NTS3 receptor, neurotensin receptor 3 (also known as NTR3 and sortilin); REM, rapid eye movement; SSRI, selective 5-HT re-uptake inhibitor; TASK-3, TWIK-related acid-sensitive K + channel 3 (also known as K2P9.1); THPP, 6,7,pyrimidine; TREK-1, TWIK-related K + channel 1(also known as K2P2.1); TST, tail suspension test IntroductionDepression is a polygenic and highly complex psychiatric disorder that is currently a major burden on society. It is highly heterogeneous in presentation and frequently exhibits high comorbidity with other psychiatric and somatic deficits. Depression is highly prevalent. It is thought to be the fourth most common cause of a worldwide of reduction in disability-adjusted life years and is predicted to become the second by 2020 (Kessler et al., 2005). The economic burden of this disease is estimated to be $53 billion per year in the United States, and more than $100 billion in Europe. The treatments available for depression are suboptimal and still unsatisfactory; less than 50% of depressed patients when treated achieve full remission. The antidepressants (ADs) currently available still have tolerability issues such as insomnia, weight gain, nausea and sexual dysfunction, which commonly lead to treatment discontinuation. All current ADs also have a slow onset of action, which may take several weeks to months to produce a therapeutic resp...

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

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Involvement of the TREK‐1 channel in human alveolar cell membrane potential and its regulation by inhibitors of the chloride current

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Potentiation of Schaffer-Collateral CA1 Synaptic Transmission by eEF2K and p38 MAPK Mediated Mechanisms

“…With regard to the potential involvement of TREK-1 in neurological diseases, it has been already shown that TREK-1 can be beneficial against mood disorders. Genetic deletion of the background potassium channel TREK-1 creates immunity to depression-inducing paradigms (Heurteaux et al, 2006; Mazella et al, 2010; Borsotto et al, 2015; Vivier et al, 2016). Therefore, these results suggest a possibility to regulate TREK-1 by specific modulation of eEF2K activity.…”