RT Journal Article
SR Electronic
T1 GABA<sub>A</sub> Receptors Expressed in Oligodendrocytes Cultured from the Neonatal Rat Contain <em>α</em>3 and <em>γ</em>1 Subunits and Present Differential Functional and Pharmacological Properties
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 133
OP 146
DO 10.1124/molpharm.120.000091
VO 99
IS 2
A1 Rainald Pablo Ordaz
A1 Edith Garay
A1 Agenor Limon
A1 Alberto Pérez-Samartín
A1 María Victoria Sánchez-Gómez
A1 Leticia Robles-Martínez
A1 Abraham Cisneros-Mejorado
A1 Carlos Matute
A1 Rogelio O. Arellano
YR 2021
UL http://molpharm.aspetjournals.org/content/99/2/133.abstract
AB Oligodendrocytes (OLs) express functional GABAA receptors (GABAARs) that are activated by GABA released at synaptic contacts with axons or by ambient GABA in extrasynaptic domains. In both instances, the receptors’ molecular identity has not been fully defined. Furthermore, data on their structural diversity in different brain regions and information on age-dependent changes in their molecular composition are scant. This lack of knowledge has delayed access to a better understanding of the role of GABAergic signaling between neurons and OLs. Here, we used functional, and pharmacological analyses, as well as gene and protein expression of GABAAR subunits, to explore the subunit combination that could explain the receptor functional profile expressed in OLs from the neonate rat. We found that GABAAR composed of α3β2γ1 subunits mimicked the characteristics of the endogenous receptor when expressed heterologously in Xenopus laevis oocytes. Either α3 or γ1 subunit silencing by small interfering RNA transfection changed the GABA-response characteristics in oligodendrocyte precursor cells, indicating their participation in the endogenous receptor conformation. Thus, α3 subunit silencing shifted the mean EC50 for GABA from 75.1 to 46.6 µM, whereas γ1 silencing reduced the current amplitude response by 55%. We also observed that β-carbolines differentially enhance GABA responses in oligodendroglia as compared with those in neurons. These results contribute to defining the molecular and pharmacological properties of GABAARs in OLs. Additionally, the identification of β-carbolines as selective enhancers of GABAARs in OLs may help to study the role of GABAergic signaling during myelination.Significance Statement GABAergic signaling through GABAA receptors (GABAARs) expressed in the oligodendroglial lineage contributes to the myelination control. Determining the molecular identity and the pharmacology of these receptors is essential to define their specific roles in myelination. Using GABAAR subunit expression and silencing, we identified that the GABAAR subunit combination α3β2γ1 conforms the bulk of GABAARs in oligodendrocytes from rat neonates. Furthermore, we found that these receptors have differential pharmacological properties that allow specific positive modulation by β-carbolines.