Interactions of L-3,5,3'-Triiodothyronine [corrected], Allopregnanolone, and Ivermectin with the GABAA Receptor: Evidence for Overlapping Intersubunit Binding Modes

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Oct 1

PMID 26421724

Citations 7

Authors

Thomas Westergard

Reza Salari

Joseph V Martin

Grace Brannigan

Affiliations

Soon will be listed here.

Abstract

Structural mechanisms of modulation of γ-aminobutyric acid (GABA) type A receptors by neurosteroids and hormones remain unclear. The thyroid hormone L-3,5,3'-triiodothyronine (T3) inhibits GABAA receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP). Here we use functional experiments on α2β1γ2 GABAA receptors expressed in Xenopus oocytes to detect competitive interactions between T3 and an agonist (ivermectin, IVM) with a crystallographically determined binding site at subunit interfaces in the transmembrane domain of a homologous receptor (glutamate-gated chloride channel, GluCl). T3 and ALLOP also show competitive effects, supporting the presence of both a T3 and ALLOP binding site at one or more subunit interfaces. Molecular dynamics (MD) simulations over 200 ns are used to investigate the dynamics and energetics of T3 in the identified intersubunit sites. In these simulations, T3 molecules occupying all intersubunit sites (with the exception of the α-β interface) display numerous energetically favorable conformations with multiple hydrogen bonding partners, including previously implicated polar/acidic sidechains and a structurally conserved deformation in the M1 backbone.

Citing Articles

Fibromyalgia pathogenesis explained by a neuroendocrine multistable model.

Demori I, Losacco S, Giordano G, Mucci V, Blanchini F, Burlando B PLoS One. 2024; 19(7):e0303573.

PMID: 38990866 PMC: 11238986. DOI: 10.1371/journal.pone.0303573.

Nongenomic roles of thyroid hormones and their derivatives in adult brain: are these compounds putative neurotransmitters?.

Martin J, Sarkar P Front Endocrinol (Lausanne). 2023; 14:1210540.

PMID: 37701902 PMC: 10494427. DOI: 10.3389/fendo.2023.1210540.

L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors.

Moffett S, Klein E, Brannigan G, Martin J PLoS One. 2019; 14(10):e0223272.

PMID: 31584962 PMC: 6777777. DOI: 10.1371/journal.pone.0223272.

Alphaxalone Binds in Inner Transmembrane β+-α- Interfaces of α1β3γ2 γ-Aminobutyric Acid Type A Receptors.

Ziemba A, Szabo A, Pierce D, Haburcak M, Stern A, Nourmahnad A Anesthesiology. 2017; 128(2):338-351.

PMID: 29210709 PMC: 5771863. DOI: 10.1097/ALN.0000000000001978.

Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin.

Chen I, Kubo Y J Physiol. 2017; 596(10):1833-1845.

PMID: 29063617 PMC: 5978302. DOI: 10.1113/JP275236.

References

Chiara D, Dangott L, Eckenhoff R, Cohen J . Identification of nicotinic acetylcholine receptor amino acids photolabeled by the volatile anesthetic halothane. Biochemistry. 2003; 42(46):13457-67. DOI: 10.1021/bi0351561. View

Obregon M, Morreale de Escobar G, Escobar del Rey F . Concentrations of triiodo-L-thyronine in the plasma and tissues of normal rats, as determined by radioimmunoassay: comparison with results obtained by an isotopic equilibrium technique. Endocrinology. 1978; 103(6):2145-53. DOI: 10.1210/endo-103-6-2145. View

Henin J, Salari R, Murlidaran S, Brannigan G . A predicted binding site for cholesterol on the GABAA receptor. Biophys J. 2014; 106(9):1938-49. PMC: 4017285. DOI: 10.1016/j.bpj.2014.03.024. View

Chapell R, Martin J, Machu T, Leidenheimer N . Direct channel-gating and modulatory effects of triiodothyronine on recombinant GABA(A) receptors. Eur J Pharmacol. 1998; 349(1):115-21. DOI: 10.1016/s0014-2999(98)00182-4. View

ARUNLAKSHANA O, SCHILD H . Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959; 14(1):48-58. PMC: 1481829. DOI: 10.1111/j.1476-5381.1959.tb00928.x. View

Lambert J, Cooper M, Simmons R, Weir C, Belelli D . Neurosteroids: endogenous allosteric modulators of GABA(A) receptors. Psychoneuroendocrinology. 2009; 34 Suppl 1:S48-58. DOI: 10.1016/j.psyneuen.2009.08.009. View

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

Yoluk O, Bromstrup T, Bertaccini E, Trudell J, Lindahl E . Stabilization of the GluCl ligand-gated ion channel in the presence and absence of ivermectin. Biophys J. 2013; 105(3):640-7. PMC: 3736686. DOI: 10.1016/j.bpj.2013.06.037. View

Covey D, Evers A, Mennerick S, Zorumski C, Purdy R . Recent developments in structure-activity relationships for steroid modulators of GABA(A) receptors. Brain Res Brain Res Rev. 2001; 37(1-3):91-7. DOI: 10.1016/s0165-0173(01)00126-6. View

10.

Mason G, Walker C, Prange Jr A . L-triiodothyronine: is this peripheral hormone a central neurotransmitter?. Neuropsychopharmacology. 1993; 8(3):253-8. DOI: 10.1038/npp.1993.28. View

11.

Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J . CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem. 2009; 31(4):671-90. PMC: 2888302. DOI: 10.1002/jcc.21367. View

12.

Krasowski M, Harrison N . General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999; 55(10):1278-303. PMC: 2854026. DOI: 10.1007/s000180050371. View

13.

Jansen M, Bali M, Akabas M . Modular design of Cys-loop ligand-gated ion channels: functional 5-HT3 and GABA rho1 receptors lacking the large cytoplasmic M3M4 loop. J Gen Physiol. 2008; 131(2):137-46. PMC: 2213565. DOI: 10.1085/jgp.200709896. View

14.

Lynagh T, Lynch J . Ivermectin binding sites in human and invertebrate Cys-loop receptors. Trends Pharmacol Sci. 2012; 33(8):432-41. DOI: 10.1016/j.tips.2012.05.002. View

15.

Murail S, Wallner B, Trudell J, Bertaccini E, Lindahl E . Microsecond simulations indicate that ethanol binds between subunits and could stabilize an open-state model of a glycine receptor. Biophys J. 2011; 100(7):1642-50. PMC: 3072665. DOI: 10.1016/j.bpj.2011.02.032. View

16.

Jansen M, Akabas M . State-dependent cross-linking of the M2 and M3 segments: functional basis for the alignment of GABAA and acetylcholine receptor M3 segments. J Neurosci. 2006; 26(17):4492-9. PMC: 6674078. DOI: 10.1523/JNEUROSCI.0224-06.2006. View

17.

Adelsberger H, Lepier A, Dudel J . Activation of rat recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptor by the insecticide ivermectin. Eur J Pharmacol. 2000; 394(2-3):163-70. DOI: 10.1016/s0014-2999(00)00164-3. View

18.

Dawson G, Wafford K, Smith A, Marshall G, Bayley P, Schaeffer J . Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the gamma-aminobutyric acid(A) receptor. J Pharmacol Exp Ther. 2000; 295(3):1051-60. View

19.

Dratman M, Futaesaku Y, Crutchfield F, Berman N, Payne B, Sar M . Iodine-125-labeled triiodothyronine in rat brain: evidence for localization in discrete neural systems. Science. 1982; 215(4530):309-12. DOI: 10.1126/science.7053582. View

20.

Klauda J, Venable R, Freites J, OConnor J, Tobias D, Mondragon-Ramirez C . Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J Phys Chem B. 2010; 114(23):7830-43. PMC: 2922408. DOI: 10.1021/jp101759q. View