Substitution of 5-HT1A receptor signaling by a light-activated G protein-coupled receptor.

The Journal of Biological Chemistry
Eugene OhStefan Herlitze

Abstract

Understanding serotonergic (5-HT) signaling is critical for understanding human physiology, behavior, and neuropsychiatric disease. 5-HT mediates its actions via ionotropic and metabotropic 5-HT receptors. The 5-HT(1A) receptor is a metabotropic G protein-coupled receptor linked to the G(i/o) signaling pathway and has been specifically implicated in the pathogenesis of depression and anxiety. To understand and precisely control 5-HT(1A) signaling, we created a light-activated G protein-coupled receptor that targets into 5-HT(1A) receptor domains and substitutes for endogenous 5-HT(1A) receptors. To induce 5-HT(1A)-like targeting, vertebrate rhodopsin was tagged with the C-terminal domain (CT) of 5-HT(1A) (Rh-CT(5-HT1A)). Rh-CT(5-HT1A) activates G protein-coupled inward rectifying K(+) channels in response to light and causes membrane hyperpolarization in hippocampal neurons, similar to the agonist-induced responses of the 5-HT(1A) receptor. The intracellular distribution of Rh-CT(5-HT1A) resembles that of the 5-HT(1A) receptor; Rh-CT(5-HT1A) localizes to somatodendritic sites and is efficiently trafficked to distal dendritic processes. Additionally, neuronal expression of Rh-CT(5-HT1A), but not Rh, decreases 5-HT(1A) agonist se...Continue Reading

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