Sci. STKE, 5 September 2006
DEPRESSION A Depressing K+ Channel?
Although drugs that selectively inhibit 5-hydroxytryptamine (5-HT, serotonin) reuptake (SSRIs) are clinically effective antidepressants, the mechanisms through which they act—and the precise role of serotonergic neurotransmission in the pathogenesis of depression—have been unclear. However, at least some effects of antidepressant therapy involve the 5-HT1A receptor [activation of which can decrease adenosine 3',5'-monophosphate (cAMP) signaling] and 5-HT1A-dependent neurogenesis. TREK-1, a potassium channel that likely plays a role in determining resting membrane potential and opposing neuronal firing, is inhibited by activation of the cAMP pathway. Noting that TREK-1 is expressed in brain regions likely to be involved in certain aspects of depression, Heurteaux et al. investigated the responses of mice lacking TREK-1 (Kcnk2–/–) in various behavioral models of depression and antidepressant activity and found that the mice acted as though they had been given antidepressants. In contrast, elimination of TRAAK, a closely related potassium channel that, unlike TREK-1 is not regulated through cAMP signaling and was not directly inhibited by SSRIs, did not produce an "antidepressant-like" phenotype. The firing rate of midbrain 5-HT neurons was increased in Kcnk2–/– mice compared with wild-type, the response of hippocampal neurons to a 5-HT1A antagonist was similar to that typical of wild-type mice chronically treated with antidepressants, and the effect of the SSRI fluoxetine on hippocampal neurogenesis was potentiated. Stress contributes to the pathogenesis of depression, and Kcnk2–/– mice showed an attenuated increase in serum corticosterone in response to stress. Thus, the authors propose that TREK-1 may represent a viable target for antidepressant therapy.
In a model discussed by Gordon and Hen, feedback of serotonin onto presynaptic 5-HT1A receptors might be expected to decrease cAMP signaling, increasing TREK-1 activity and thereby decreasing neuronal firing and serotonin release. In this model, TREK-1 loss would disrupt this negative feedback loop, thereby increasing serotonin release and thus exerting an antidepressant-like effect.
C. Heurteaux, G. Lucas, N. Guy, M. El Yacoubi, S. Thümmler, X.-D. Peng, F. Noble, N. Blondeau, C. Widmann, M. Borsotto, G. Gobbi, J. M. Vaugeois, G. Debonnel, M. Lazdunski, Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat. Neurosci. 9, 1134-1141 (2006). [PubMed]
J. A. Gordon, R. Hen, TREKing toward new antidepressants. Nat. Neurosci. 9, 1081-1083 (2006). [PubMed]
Citation: A Depressing K+ Channel? Sci. STKE 2006, tw303 (2006).
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