Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Neurosteroids (NS) are the main modulators of γ-aminobutyric acid type A receptors (GABAARs), which are the ligand-gated channels target of the major inhibitory neurotransmitter in vertebrates. As a consequence of their ability to modify inhibitory functions in the brain, NS have high physiological and clinical relevance. Accumulated evidence has strongly suggested that NS binding sites were located in the GABAAR transmembrane domain; however the specific localization of these sites has remained an enigma for decades. Fortunately, recent resolution of GABAARs crystal structures, together with computational strategies applied to investigate the NS binding, has paved the way to rationalizing the molecular basis of NS modulation. This work reviews from a historical perspective the road followed for establishing the GABAAR/NS binding mode, from their initial molecular modeling to the latest findings. Furthermore, a comparative analysis describing the NS binding is provided, plus a preliminary analysis of putative NS sites in other assemblies. © 2018 American Chemical Society.

Registro:

Documento: Artículo
Título:In Search of GABAA Receptor's Neurosteroid Binding Sites
Autor:Alvarez, L.D.; Pecci, A.; Estrin, D.A.
Filiación:Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina
Departamento de Química Inorgánica Analítica y Química Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina
UMYMFOR, CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina
IFIBYNE, CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina
INQUIMAE, CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina
Año:2018
DOI: http://dx.doi.org/10.1021/acs.jmedchem.8b01400
Título revista:Journal of Medicinal Chemistry
Título revista abreviado:J. Med. Chem.
ISSN:00222623
CODEN:JMCMA
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v_n_p_Alvarez

Referencias:

  • Jembrek, M.J., Vlainić, J., GABA Receptors: Pharmacological Potential and Pitfalls (2015) Curr. Pharm. Des., 21 (34), pp. 4943-4959
  • Enna, S.J., Enna, S.J., Möhler, H., The GABA Receptors (2007) The GABA Receptors, pp. 1-21. , Eds. Humana Press: Totowa, NJ
  • Wang, M., Neurosteroids and GABAA Receptor Function (2011) Front. Endocrinol. (Lausanne, Switz.), 2, pp. 1-23
  • Belelli, D., Lambert, J.J., Neurosteroids: Endogenous Regulators of the GABAA Receptor (2005) Nat. Rev. Neurosci., 6, p. 565
  • Braat, S., Kooy, R.F., The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders (2015) Neuron, 86 (5), pp. 1119-1130
  • Rudolph, U., Möhler, H., GABAA Receptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism (2014) Annu. Rev. Pharmacol. Toxicol., 54 (1), pp. 483-507
  • Reddy, D.S., Estes, W.A., Clinical Potential of Neurosteroids for CNS Disorders (2016) Trends Pharmacol. Sci., 37 (7), pp. 543-561
  • Zorumski, C.F., Paul, S.M., Izumi, Y., Covey, D.F., Mennerick, S., Neurosteroids, Stress and Depression: Potential Therapeutic Opportunities (2013) Neurosci. Biobehav. Rev., 37 (1), pp. 109-122
  • Blanco, M.J., La, D., Coughlin, Q., Newman, C.A., Griffin, A.M., Harrison, B.L., Salituro, F.G., Breakthroughs in Neuroactive Steroid Drug Discovery (2018) Bioorg. Med. Chem. Lett., 28 (2), pp. 61-70
  • Miller, P.S., Smart, T.G., Binding, Activation and Modulation of Cys-Loop Receptors (2010) Trends Pharmacol. Sci., 31 (4), pp. 161-174
  • Olsen, R.W., Sieghart, W., GABAA Receptors: Subtypes Provide Diversity of Function and Pharmacology (2009) Neuropharmacology, 56 (1), pp. 141-148
  • Engin, E., Benham, R.S., Rudolph, U., An Emerging Circuit Pharmacology of GABAA Receptors (2018) Trends Pharmacol. Sci., 39 (8), pp. 710-732
  • Puthenkalam, R., Hieckel, M., Simeone, X., Suwattanasophon, C., Feldbauer, R.V., Ecker, G.F., Ernst, M., Structural Studies of GABAA Receptor Binding Sites: Which Experimental Structure Tells Us What? (2016) Front. Mol. Neurosci., 9, pp. 1-20
  • Olsen, R.W., GABAA Receptor: Positive and Negative Allosteric Modulators (2018) Neuropharmacology, 136, pp. 10-22
  • Sieghart, W., Allosteric Modulation of GABAA Receptors via Multiple Drug-Binding Sites (2015) Adv. Pharmacol., 72, pp. 53-96
  • Carver, C.M., Reddy, D.S., Neurosteroid Interactions with Synaptic and Extrasynaptic GABAA Receptors: Regulation of Subunit Plasticity, Phasic and Tonic Inhibition, and Neuronal Network Excitability (2013) Psychopharmacology (Berl)., 230 (2), pp. 151-188
  • Veleiro, A.S., Burton, G., Structure-Activity Relationships of Neuroactive Steroids Acting on the GABAA Receptor (2009) Curr. Med. Chem., 16 (4), pp. 455-472
  • Miller, P.S., Scott, S., Masiulis, S., De Colibus, L., Pardon, E., Steyaert, J., Aricescu, A.R., Structural Basis for GABAA Receptor Potentiation by Neurosteroids (2017) Nat. Struct. Mol. Biol., 24 (11), pp. 986-992
  • Laverty, D., Thomas, P., Field, M., Andersen, O.J., Gold, M.G., Biggin, P.C., Gielen, M., Smart, T.G., Crystal Structures of a GABAA Receptor Chimera Reveal New Endogenous Neurosteroid-Binding Sites (2017) Nat. Struct. Mol. Biol., 24 (11), pp. 977-985
  • Alvarez, L.D., Estrin, D.A., Exploring the Molecular Basis of Neurosteroid Binding to the β3 Homopentameric GABAA Receptor (2015) J. Steroid Biochem. Mol. Biol., 154, pp. 159-167
  • Alvarez, L.D., Pecci, A., Structure and Dynamics of Neurosteroid Binding to the α1β2γ2 GABAA Receptor (2018) J. Steroid Biochem. Mol. Biol., 182, pp. 72-80
  • Hosie, A.M., Wilkins, M.E., Da Silva, H.M.A., Smart, T.G., Endogenous Neurosteroids Regulate GABAA Receptors through Two Discrete Transmembrane Sites (2006) Nature, 444 (7118), pp. 486-489
  • Mihic, S.J., Ye, Q., Wick, M.J., Koltchine, V.V., Krasowski, M.D., Finn, S.E., Mascia, M.P., Harrison, N.L., Sites of Alcohol and Volatile Anaesthetic Action on GABAA and Glycine Receptors (1997) Nature, 389 (6649), pp. 385-389
  • Bali, M., Akabas, M.H., Defining the Propofol Binding Site Location on the GABAA Receptor (2004) Mol. Pharmacol., 65 (1), pp. 68-76
  • Chang, C.S.S., Olcese, R., Olsen, R.W., A Single M1 Residue in the β2 Subunit Alters Channel Gating of GABAA Receptor in Anesthetic Modulation and Direct Activation (2003) J. Biol. Chem., 278 (44), pp. 42821-42828
  • Jurd, R., Arras, M., Lambert, S., Drexler, B., Siegwart, R., Crestani, F., Zaugg, M., Rudolph, U., General Anesthetic Actions in Vivo Strongly Attenuated by a Point Mutation in the GABA(A) Receptor Beta3 Subunit (2003) FASEB J., 17 (2), pp. 250-252
  • Hosie, A.M., Wilkins, M.E., Smart, T.G., Neurosteroid Binding Sites on GABAA Receptors (2007) Pharmacol. Ther., 116 (1), pp. 7-19
  • Akk, G., Li, P., Bracamontes, J., Reichert, D.E., Covey, D.F., Steinbach, J.H., Mutations of the GABAA Receptor Alpha1 Subunit M1 Domain Reveal Unexpected Complexity for Modulation by Neuroactive Steroids (2008) Mol. Pharmacol., 74 (3), pp. 614-627
  • Hosie, A.M., Clarke, L., Da Silva, H., Smart, T.G., Conserved Site for Neurosteroid Modulation of GABAA Receptors (2009) Neuropharmacology, 56 (1), pp. 149-154
  • Bracamontes, J.R., Li, P., Akk, G., Steinbach, J.H., A Neurosteroid Potentiation Site Can Be Moved among GABAA Receptor Subunits (2012) J. Physiol., 590 (22), pp. 5739-5747
  • Williams, D.B., A Mutant Residue in the Third Transmembrane Region of the GABAA Alpha1 Subunit Causes Increased Agonistic Neurosteroid Responses (2011) Neurochem. Int., 58 (7), pp. 794-803
  • Li, G.D., Chiara, D.C., Cohen, J.B., Olsen, R.W., Neurosteroids Allosterically Modulate Binding of the Anesthetic Etomidate to γ-Aminobutyric Acid Type A Receptors (2009) J. Biol. Chem., 284 (18), pp. 11771-11775
  • Chen, Z.W., Manion, B., Townsend, R.R., Reichert, D.E., Covey, D.F., Steinbach, J.H., Sieghart, W., Evers, A.S., Neurosteroid Analog Photolabeling of a Site in the Third Transmembrane Domain of the β3 Subunit of the GABAA Receptor (2012) Mol. Pharmacol., 82 (3), pp. 408-419
  • Li, G.-D., Chiara, D.C., Sawyer, G.W., Husain, S.S., Olsen, R.W., Cohen, J.B., Identification of a GABAA Receptor Anesthetic Binding Site at Subunit Interfaces by Photolabeling with an Etomidate Analog (2006) J. Neurosci., 26 (45), pp. 11599-11605
  • Hibbs, R.E., Gouaux, E., Principles of Activation and Permeation in an Anion-Selective Cys-Loop Receptor (2011) Nature, 474 (7349), pp. 54-60
  • Miller, P.S., Aricescu, A.R., Crystal Structure of a Human GABAA Receptor (2014) Nature, 512 (7514), pp. 270-275
  • Krishnan, K., Manion, B.D., Taylor, A., Bracamontes, J., Steinbach, J.H., Reichert, D.E., Evers, A.S., Covey, D.F., Neurosteroid Analogues. 17. Inverted Binding Orientations of Androsterone Enantiomers at the Steroid Potentiation Site on γ-Aminobutyric Acid Type A Receptors (2012) J. Med. Chem., 55 (3), pp. 1334-1345
  • Davies, P.A., Kirkness, E.F., Hales, T.G., Modulation by General Anaesthetics of Rat GABAA Receptors Comprised of α1β3 and β3 Subunits Expressed in Human Embryonic Kidney 293 Cells (1997) Br. J. Pharmacol., 120 (5), pp. 899-909
  • Chen, Q., Wells, M.M., Arjunan, P., Tillman, T.S., Cohen, A.E., Xu, Y., Tang, P., Structural Basis of Neurosteroid Anesthetic Action on GABAA Receptors (2018) Nat. Commun., 9 (1), p. 3972
  • Zhu, S., Noviello, C.M., Teng, J., Walsh, R.M., Kim, J.J., Hibbs, R.E., Structure of a Human Synaptic GABAA Receptor (2018) Nature, 559 (7712), pp. 67-72
  • Phulera, S., Zhu, H., Yu, J., Claxton, D.P., Yoder, N., Yoshioka, C., Gouaux, E., Cryo-EM Structure of the Benzodiazepine-Sensitive δ1β1γ2S Tri-Heteromeric GABAA Receptor in Complex with GABA (2018) ELife, 7, p. e39383
  • Miller, P., Masiulis, S., Malinauskas, T., Kotecha, A., Rao, S., Chavali, S., De Colibus, L., Aricescu, R., Heteromeric GABAA Receptor Structures in Positively-Modulated Active States (2018) BioRxiv, p. 338343
  • Chisari, M., Eisenman, L.N., Covey, D.F., Mennerick, S., Zorumski, C.F., The Sticky Issue of Neurosteroids and GABAA Receptors (2010) Trends Neurosci., 33 (7), pp. 299-306
  • Weir, C.J., Ling, A.T.Y., Belelli, D., Wildsmith, J.A.W., Peters, J.A., Lambert, J.J., The Interaction of Anaesthetic Steroids with Recombinant Glycine and GABAA Receptors (2004) Br. J. Anaesth., 92 (5), pp. 704-711
  • Jiang, P., Yang, C.-X., Wang, Y.-T., Xu, T.-L., Mechanisms of Modulation of Pregnanolone on Glycinergic Response in Cultured Spinal Dorsal Horn Neurons of Rat (2006) Neuroscience, 141 (4), pp. 2041-2050
  • Reddy, D.S., GABAA Receptors Mediate Tonic Inhibition and Neurosteroid Sensitivity in the Brain (2018) Vitam. Horm., 107, pp. 177-191
  • Carver, C.M., Reddy, D.S., Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors (2016) J. Pharmacol. Exp. Ther., 357 (1), pp. 188-204
  • Bracamontes, J.R., Steinbach, J.H., Steroid Interaction with a Single Potentiating Site Is Sufficient to Modulate GABA-A Receptor Function (2009) Mol. Pharmacol., 75 (4), pp. 973-981
  • Bracamontes, J., McCollum, M., Esch, C., Li, P., Ann, J., Steinbach, J.H., Akk, G., Occupation of Either Site for the Neurosteroid Allopregnanolone Potentiates the Opening of the GABAA Receptor Induced from Either Transmitter Binding Site (2011) Mol. Pharmacol., 80 (1), pp. 79-86
  • Martinez Botella, G., Salituro, F.G., Harrison, B.L., Beresis, R.T., Bai, Z., Blanco, M.J., Belfort, G.M., Robichaud, A.J., Neuroactive Steroids. 2. 3α-Hydroxy-3β-Methyl-21-(4-Cyano-1H-Pyrazol-1′-Yl)-19-nor-5β-Pregnan-20-One (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)A Receptor (2017) J. Med. Chem., 60 (18), pp. 7810-7819

Citas:

---------- APA ----------
Alvarez, L.D., Pecci, A. & Estrin, D.A. (2018) . In Search of GABAA Receptor's Neurosteroid Binding Sites. Journal of Medicinal Chemistry.
http://dx.doi.org/10.1021/acs.jmedchem.8b01400
---------- CHICAGO ----------
Alvarez, L.D., Pecci, A., Estrin, D.A. "In Search of GABAA Receptor's Neurosteroid Binding Sites" . Journal of Medicinal Chemistry (2018).
http://dx.doi.org/10.1021/acs.jmedchem.8b01400
---------- MLA ----------
Alvarez, L.D., Pecci, A., Estrin, D.A. "In Search of GABAA Receptor's Neurosteroid Binding Sites" . Journal of Medicinal Chemistry, 2018.
http://dx.doi.org/10.1021/acs.jmedchem.8b01400
---------- VANCOUVER ----------
Alvarez, L.D., Pecci, A., Estrin, D.A. In Search of GABAA Receptor's Neurosteroid Binding Sites. J. Med. Chem. 2018.
http://dx.doi.org/10.1021/acs.jmedchem.8b01400