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
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
Дата издания: 04.09.2023