A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition

NEUROPHARMACOLOGY

卷:108

Article

Jiang, Xiaoping¹  Shu, Hong-Jin¹  Krishnan, Kathiresan²  Qian, Mingxing²  Taylor, Amanda A.¹  Covey, Douglas F.^2,4,5  Zorumski, Charles F.^1,3,5  Mennerick, Steven^1,3,5 

[1] Washington Univ, Sch Med, Dept Psychiat, 660 S Euclid Ave,Campus Box 8134, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dev Biol, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Neurosci, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Anesthesiol, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Taylor Family Inst Innovat Psychiat Res, St Louis, MO 63110 USA

关键词: GABA(A) receptor;    Anesthetic;    Anxiolytic;    Inhibition;    Golgi;    Synaptic;   

DOI  :  10.1016/j.neuropharm.2016.04.031

来源: Elsevier

【 摘 要 】

Anesthetic, GABA-active neurosteroids potently augment GABA(A) receptor function, leading to important behavioral consequences. Neurosteroids and their synthetic analogues are also models for a wide variety of cell-permeant neuroactive compounds. Cell permeation and compartmentalization raise the possibility that these compounds' actions are influenced by their cellular partitioning, but these contributions are not typically considered experimentally or therapeutically. To examine the interplay between cellular accumulation and pharmacodynamics of neurosteroids, we synthesized a novel chemical biology analogue (bio-active, clickable photolabel) of GABA-active neurosteroids. We discovered that the analogue selectively photo-labels neuronal Golgi in rat hippocampal neurons. The active analogue's selective distribution was distinct from endogenous cholesterol and not completely shared by some non-GABA active, neurosteroid-like analogues. On the other hand, the distribution was not enantioselective and did not require energy, in contrast to other recent precedents from the literature. We demonstrate that the soma-selective accumulation can act as a sink or source for steroid actions at plasma-membrane GABA receptors, altering steady-state and time course of effects at somatic GABAA receptors relative to dendritic receptors. Our results suggest a novel mechanism for compartment-selective drug actions at plasma-membrane receptors. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

Free