Sugasawa Y , Cheng WW , Bracamontes JR , Chen ZW , Wang L , Germann AL , Pierce SR , Senneff TC , Krishnan K , Reichert DE , Covey DF , Akk G , Evers AS .

K08 GM126336 NIGMS NIH HHS , 5K08GM126336-03 NIH HHS , R01 GM108799 NIGMS NIH HHS , 5R01GM108580-06 NIH HHS , 2R01GM108799-05 NIH HHS , R01 GM108580 NIGMS NIH HHS

Figure 2. Neurosteroids promote steady-state desensitization of α1β3 GABAARs. Representative traces showing the effects of KK148, KK150 and epi-allopregnanolone (3β5αP) on maximal steady-state GABA-elicited currents. α1β3 GABAARs expressed in Xenopus laevis oocytes were activated with 1 mM GABA to maximally activate GABAAR current. (A–C) The effect of KK148 (10 μM), KK150 (10 μM) and 3β5αP (3 μM) on steady-state current. (D) The effect of 3β5αP (3 μM) on steady-state current in α1β3 GABAARs containing the α1V256S mutation, known to eliminate NS-induced desensitization. The results show that 3β5αP and KK148 reduce steady-state currents, consistent with enhanced desensitization, whereas KK150 does not. The effect of 3β5αP on steady-state currents is eliminated by the α1V256S mutation, consistent with 3β5αP enhancing desensitization rather than producing channel block.

Abramian, Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors. 2014, Pubmed

Abramian, Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors. 2014, Pubmed
Akk, Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit. 2001, Pubmed
Akk, Mechanisms of neurosteroid interactions with GABA(A) receptors. 2007, Pubmed
Akk, Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids. 2008, Pubmed
Akk, Kinetic and structural determinants for GABA-A receptor potentiation by neuroactive steroids. 2010, Pubmed
Akk, Enhancement of Muscimol Binding and Gating by Allosteric Modulators of the GABAA Receptor: Relating Occupancy to State Functions. 2020, Pubmed
Akk, Neuroactive steroids have multiple actions to potentiate GABAA receptors. 2004, Pubmed
Basak, Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel. 2017, Pubmed
Belelli, Neurosteroids: endogenous regulators of the GABA(A) receptor. 2005, Pubmed
Bianchi, Neurosteroids shift partial agonist activation of GABA(A) receptor channels from low- to high-efficacy gating patterns. 2003, Pubmed
Bracamontes, Steroid interaction with a single potentiating site is sufficient to modulate GABA-A receptor function. 2009, Pubmed , Xenbase
Budelier, Photoaffinity labeling with cholesterol analogues precisely maps a cholesterol-binding site in voltage-dependent anion channel-1. 2017, Pubmed
Budelier, Common binding sites for cholesterol and neurosteroids on a pentameric ligand-gated ion channel. 2019, Pubmed
Bylund, Radioligand-binding methods for membrane preparations and intact cells. 2004, Pubmed
Bylund, Radioligand binding methods: practical guide and tips. 1993, Pubmed
Chakrabarti, Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed α1β2γ2L GABA(A) Receptors. 2016, Pubmed
Chang, Desensitization mechanism of GABA receptors revealed by single oocyte binding and receptor function. 2002, Pubmed , Xenbase
Chen, Multiple functional neurosteroid binding sites on GABAA receptors. 2019, Pubmed , Xenbase
Chen, Structural basis of neurosteroid anesthetic action on GABAA receptors. 2018, Pubmed , Xenbase
Cheng, Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC. 2018, Pubmed
Comenencia-Ortiz, Phosphorylation of GABAA receptors influences receptor trafficking and neurosteroid actions. 2014, Pubmed
Das, Aliphatic diazirines as photoaffinity probes for proteins: recent developments. 2011, Pubmed
Dostalova, Human α1β3γ2L gamma-aminobutyric acid type A receptors: High-level production and purification in a functional state. 2014, Pubmed
Eaton, Multiple Non-Equivalent Interfaces Mediate Direct Activation of GABAA Receptors by Propofol. 2016, Pubmed
Edgar, MUSCLE: a multiple sequence alignment method with reduced time and space complexity. 2004, Pubmed
Evers, A synthetic 18-norsteroid distinguishes between two neuroactive steroid binding sites on GABAA receptors. 2010, Pubmed , Xenbase
Farrant, Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. 2005, Pubmed
Feng, Comparison of αβδ and αβγ GABAA receptors: Allosteric modulation and identification of subunit arrangement by site-selective general anesthetics. 2018, Pubmed
Germann, Steady-State Activation and Modulation of the Concatemeric α1β2γ2L GABAA Receptor. 2019, Pubmed , Xenbase
Germann, Steady-state activation and modulation of the synaptic-type α1β2γ2L GABAA receptor by combinations of physiological and clinical ligands. 2019, Pubmed , Xenbase
Gielen, The dual-gate model for pentameric ligand-gated ion channels activation and desensitization. 2018, Pubmed
Grobin, Perinatal allopregnanolone influences prefrontal cortex structure, connectivity and behavior in adult rats. 2006, Pubmed
Gunduz-Bruce, Trial of SAGE-217 in Patients with Major Depressive Disorder. 2019, Pubmed
Haage, Neurosteroid modulation of synaptic and GABA-evoked currents in neurons from the rat medial preoptic nucleus. 1999, Pubmed
Harrison, Modulation of the GABA receptor complex by a steroid anaesthetic. 1984, Pubmed
Harrison, A steroid anesthetic prolongs inhibitory postsynaptic currents in cultured rat hippocampal neurons. 1987, Pubmed
Harrison, Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex. 1987, Pubmed
Hosie, Conserved site for neurosteroid modulation of GABA A receptors. 2009, Pubmed
Hosie, Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. 2006, Pubmed
Jansen, Modular design of Cys-loop ligand-gated ion channels: functional 5-HT3 and GABA rho1 receptors lacking the large cytoplasmic M3M4 loop. 2008, Pubmed , Xenbase
Jayakar, Identifying Drugs that Bind Selectively to Intersubunit General Anesthetic Sites in the α1β3γ2 GABAAR Transmembrane Domain. 2019, Pubmed
Jayakar, Photoaffinity labeling identifies an intersubunit steroid-binding site in heteromeric GABA type A (GABAA) receptors. 2020, Pubmed
Jiang, A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition. 2016, Pubmed , Xenbase
Jones, The impact of receptor desensitization on fast synaptic transmission. 1996, Pubmed
Jones, Desensitized states prolong GABAA channel responses to brief agonist pulses. 1995, Pubmed
Kharasch, Steroid Anesthesia Revisited: Again. 2015, Pubmed
Kim, Shared structural mechanisms of general anaesthetics and benzodiazepines. 2020, Pubmed
Lange, Active membrane cholesterol as a physiological effector. 2016, Pubmed
Laverty, Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer. 2019, Pubmed
Laverty, Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. 2017, Pubmed
Lee, CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. 2016, Pubmed
Li, Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. 2006, Pubmed
Li, Neurosteroid migration to intracellular compartments reduces steroid concentration in the membrane and diminishes GABA-A receptor potentiation. 2007, Pubmed
Lorent, Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape. 2020, Pubmed
Lundgren, Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3beta-hydroxy-5alpha-pregnan-20-one (isoallopregnanolone). 2003, Pubmed
Masiulis, GABAA receptor signalling mechanisms revealed by structural pharmacology. 2019, Pubmed
McGibbon, MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories. 2015, Pubmed
Meng, Tools for integrated sequence-structure analysis with UCSF Chimera. 2006, Pubmed
Meslamani, Assessing the geometric diversity of cytochrome P450 ligand conformers by hierarchical clustering with a stop criterion. 2009, Pubmed
Miller, Crystal structure of a human GABAA receptor. 2014, Pubmed
Miller, Structural basis for GABAA receptor potentiation by neurosteroids. 2017, Pubmed
Mitchell, Neurosteroid modulation of GABAA receptors: molecular determinants and significance in health and disease. 2008, Pubmed
O'Boyle, Open Babel: An open chemical toolbox. 2011, Pubmed
Olsen, GABAA receptor: Positive and negative allosteric modulators. 2018, Pubmed
Olsen, International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. 2008, Pubmed
Overstreet, Slow desensitization regulates the availability of synaptic GABA(A) receptors. 2000, Pubmed
Park-Chung, Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites. 1999, Pubmed , Xenbase
Reddy, Clinical Potential of Neurosteroids for CNS Disorders. 2016, Pubmed
Represa, Trophic actions of GABA on neuronal development. 2005, Pubmed
Sali, Comparative protein modelling by satisfaction of spatial restraints. 1993, Pubmed
Seljeset, Probing GABAA receptors with inhibitory neurosteroids. 2018, Pubmed
Shen, Statistical potential for assessment and prediction of protein structures. 2006, Pubmed
Shen, Pregnenolone sulfate modulates inhibitory synaptic transmission by enhancing GABA(A) receptor desensitization. 2000, Pubmed
Sieghart, Allosteric modulation of GABAA receptors via multiple drug-binding sites. 2015, Pubmed
Sigel, Structure, function, and modulation of GABA(A) receptors. 2012, Pubmed
Smith, Neurosteroid regulation of GABA(A) receptors: Focus on the alpha4 and delta subunits. 2007, Pubmed
Steinbach, Modulation of GABA(A) receptor channel gating by pentobarbital. 2001, Pubmed
Stewart, Tryptophan mutations at azi-etomidate photo-incorporation sites on alpha1 or beta2 subunits enhance GABAA receptor gating and reduce etomidate modulation. 2008, Pubmed , Xenbase
Sugasawa, The molecular determinants of neurosteroid binding in the GABA(A) receptor. 2019, Pubmed
Tong, Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel. 2019, Pubmed
Trott, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. 2010, Pubmed
Ueno, Endogenous subunits can cause ambiguities in the pharmacology of exogenous gamma-aminobutyric acidA receptors expressed in human embryonic kidney 293 cells. 1996, Pubmed
Vauquelin, Radioligand binding to intact cells as a tool for extended drug screening in a representative physiological context. 2015, Pubmed
Wang, 3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists. 2002, Pubmed , Xenbase
Zhu, Neurosteroid prolongs GABAA channel deactivation by altering kinetics of desensitized states. 1997, Pubmed
Zhu, Structure of a human synaptic GABAA receptor. 2018, Pubmed
Ziemba, Alphaxalone Binds in Inner Transmembrane β+-α- Interfaces of α1β3γ2 γ-Aminobutyric Acid Type A Receptors. 2018, Pubmed , Xenbase
Zorumski, Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. 2019, Pubmed
van Meer, Membrane lipids: where they are and how they behave. 2008, Pubmed