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A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition.
Jiang X
,
Shu HJ
,
Krishnan K
,
Qian M
,
Taylor AA
,
Covey DF
,
Zorumski CF
,
Mennerick S
.
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Anesthetic, GABA-active neurosteroids potently augment GABAA 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.
Akk,
Neurosteroid access to the GABAA receptor.
2005, Pubmed
Akk,
Neurosteroid access to the GABAA receptor.
2005,
Pubmed
Alakoskela,
Lack of enantiomeric specificity in the effects of anesthetic steroids on lipid bilayers.
2007,
Pubmed
Antkowiak,
How do general anaesthetics work?
2001,
Pubmed
Belelli,
Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance.
2006,
Pubmed
Belelli,
Neurosteroids: endogenous regulators of the GABA(A) receptor.
2005,
Pubmed
Boudes,
Best1 is a gene regulated by nerve injury and required for Ca2+-activated Cl- current expression in axotomized sensory neurons.
2009,
Pubmed
Brown,
Developmentally regulated neurosteroid synthesis enhances GABAergic neurotransmission in mouse thalamocortical neurones.
2015,
Pubmed
Chen,
Neurosteroid analog photolabeling of a site in the third transmembrane domain of the β3 subunit of the GABA(A) receptor.
2012,
Pubmed
Chen,
A neurosteroid analogue photolabeling reagent labels the colchicine-binding site on tubulin: a mass spectrometric analysis.
2012,
Pubmed
Chisari,
The influence of neuroactive steroid lipophilicity on GABAA receptor modulation: evidence for a low-affinity interaction.
2009,
Pubmed
,
Xenbase
Chisari,
The sticky issue of neurosteroids and GABA(A) receptors.
2010,
Pubmed
Covey,
ent-Steroids: novel tools for studies of signaling pathways.
2009,
Pubmed
Drin,
Topological regulation of lipid balance in cells.
2014,
Pubmed
Dubinsky,
Diazirine based photoaffinity labeling.
2012,
Pubmed
Eisenman,
Anticonvulsant and anesthetic effects of a fluorescent neurosteroid analog activated by visible light.
2007,
Pubmed
Eshaq,
GABA acts as a ligand chaperone in the early secretory pathway to promote cell surface expression of GABAA receptors.
2010,
Pubmed
Gimpl,
Cholesterol reporter molecules.
2007,
Pubmed
Harrison,
Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex.
1987,
Pubmed
Hirota,
Amino acid residues critical for endoplasmic reticulum export and trafficking of platelet-activating factor receptor.
2010,
Pubmed
Hofmann,
A novel alkyne cholesterol to trace cellular cholesterol metabolism and localization.
2014,
Pubmed
Hou,
The impact of click chemistry in medicinal chemistry.
2012,
Pubmed
Huettner,
Primary culture of identified neurons from the visual cortex of postnatal rats.
1986,
Pubmed
Inquimbert,
Regional differences in the decay kinetics of GABA(A) receptor-mediated miniature IPSCs in the dorsal horn of the rat spinal cord are determined by mitochondrial transport of cholesterol.
2008,
Pubmed
Jao,
Bioorthogonal probes for imaging sterols in cells.
2015,
Pubmed
Lapinsky,
Tandem photoaffinity labeling-bioorthogonal conjugation in medicinal chemistry.
2012,
Pubmed
Li,
Neurosteroid migration to intracellular compartments reduces steroid concentration in the membrane and diminishes GABA-A receptor potentiation.
2007,
Pubmed
Marks,
Endocytosis and sorting of glycosphingolipids in sphingolipid storage disease.
2002,
Pubmed
Mennerick,
Passive and synaptic properties of hippocampal neurons grown in microcultures and in mass cultures.
1995,
Pubmed
Mukherjee,
Cholesterol distribution in living cells: fluorescence imaging using dehydroergosterol as a fluorescent cholesterol analog.
1998,
Pubmed
Peyrot,
Tracking the subcellular fate of 20(s)-hydroxycholesterol with click chemistry reveals a transport pathway to the Golgi.
2014,
Pubmed
Qian,
Neurosteroid analogues. 18. Structure-activity studies of ent-steroid potentiators of γ-aminobutyric acid type A receptors and comparison of their activities with those of alphaxalone and allopregnanolone.
2014,
Pubmed
,
Xenbase
Quassollo,
A RhoA Signaling Pathway Regulates Dendritic Golgi Outpost Formation.
2015,
Pubmed
Sheldahl,
Estrogen induces rapid translocation of estrogen receptor beta, but not estrogen receptor alpha, to the neuronal plasma membrane.
2008,
Pubmed
Shu,
Slow actions of neuroactive steroids at GABAA receptors.
2004,
Pubmed
,
Xenbase
Shu,
Photodynamic effects of steroid-conjugated fluorophores on GABAA receptors.
2009,
Pubmed
,
Xenbase
Shu,
Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions.
2007,
Pubmed
,
Xenbase
Sooksawate,
Increased membrane cholesterol reduces the potentiation of GABA(A) currents by neurosteroids in dissociated hippocampal neurones.
1998,
Pubmed
Steinbach,
Modulation of GABA(A) receptor channel gating by pentobarbital.
2001,
Pubmed
Stell,
Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors.
2003,
Pubmed
Tokuda,
Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis.
2010,
Pubmed
Viertler,
Activity based subcellular resolution imaging of lipases.
2012,
Pubmed
Wafford,
Novel compounds selectively enhance delta subunit containing GABA A receptors and increase tonic currents in thalamus.
2009,
Pubmed
Wohlfarth,
Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the delta subunit.
2002,
Pubmed
Zorumski,
Neurosteroids, stress and depression: potential therapeutic opportunities.
2013,
Pubmed
Zorumski,
Potential clinical uses of neuroactive steroids.
2000,
Pubmed
van Meer,
Membrane lipids and vesicular traffic.
2004,
Pubmed
