Corticosteroids as Selective and Effective Modulators of Glycine Receptors

Elena I. Solntseva, Elena I. Solntseva, Julia V. Bukanova Rodion Kondratenko and Eva KudovaACS Chem. Neurosci. August 16,2023 https://doi.org/10.1021/acschemneuro.3c00287 

he mechanismof the negativeimpactof corticosteroidson the inductionand progressof mentalillnessremainsunclear.In this work,we studiedthe effectsof corticosteroidson the activityof neuronalglycinereceptors(GlyR)and GABA-Areceptors(GABAAR) by measuringthe chloridecurrentinducedby the applicationof GABA(2 or 5μM)  to isolatedcerebellarPurkinjecells (IGABA) and by the applicationof glycine(100μM) to pyramidalneuronsof the rat hippocampus(IGly). It was foundthat corticosterone,5α-dihydrodeoxycorticosterone,allotetrahydrocorticosterone,cortisol,and 17α,21-dihydroxypregnenolonewereable to acceleratethe desensitizationof theIGlyat physiologicalconcentrations(IC50valuesvaryingfrom 0.39 to 0.72μM).Next,cortisone,11-deoxycortisol,11-deoxycorticosterone,5β-dihydrodeoxycorticosterone,and tetrahydrocorticosteroneacceleratedthedesensitizationofIGlywith IC50valuesvaryingfrom 10.3 to 15.2μM.  Allotetrahydrocorticosteroneand tetrahydrocorticosteronepotentiatedtheIGABAalbeitwith high EC50values(18−23μM).The rest of the steroidshad no effectonIGABAin the rangeofconcentrationsof 1−100μM. Finally,our studyhas suggesteda structuralrelationshipof the 3β-hydroxylgroup/3-oxogroupwiththe selectivemodulatoryactivityon GlyRsin contrastto the 3α-hydroxylgroupthat is pivotalfor GABAARs. In summary,our resultssuggestthat increasedGlyR desensitizationby corticosteroidsmay contributeto brain dysfunctionunderchronicstressand identifycorticosteroidsfor furtherdevelopmentas selectivemodulatorsof GlyRs