Single molecule analysis of serotonin transporter regulation using antagonist-conjugated quantum dots reveals restricted, p38 MAPK-dependent mobilization underlying uptake activation.

[gm1 gangliosidosis]

The presynaptic serotonin (5 -HT ) transporter (SERT ) is targeted by widely prescribed antidepressant medications . Altered SERT expression or regulation has been implicated in multiple neuropsychiatric disorders , including anxiety , depression and autism . Here , we implement a generalizable strategy that exploits antagonist-conjugated quantum dots (Qdots ) to monitor , for the first time , single SERT proteins on the surface of serotonergic cells . We document two pools of SERT proteins defined by lateral mobility , one that exhibits relatively free diffusion , and a second , localized to cholesterol and GM 1 ganglioside-enriched microdomains , that displays restricted mobility . Receptor-linked signaling pathways that enhance SERT activity mobilize transporters that , nonetheless , remain confined to membrane microdomains . Mobilization of transporters arises from a p 38 MAPK-dependent untethering of the SERT C terminus from the juxtamembrane actin cytoskeleton . Our studies establish the utility of ligand-conjugated Qdots for analysis of the behavior of single membrane proteins and reveal a physical basis for signaling-mediated SERT regulation .

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gm1 gangliosidosis

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