GABAA receptor modulation by acetone

PARLATO ML; LÓPEZ PAZOS MI; DEL VAS M; AN BELTRÁN GONZÁLEZ; CALVO DJ

Modalidad virtual

Congreso; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; 2021

Sociedad Argentina de Biofísica

Ketogenesis is a metabolic process that generates ketone bodies (acetone, acetoacetate and β-hydroxybutyrate) from the β-oxidation of fatty acids. Ketogenic pathway occurs sporadically under normal conditions, but is positively regulated when carbohydrate stores decrease significantly or by increases in the concentration of fatty acids, for example during fasting, prolonged exercise, excessive alcohol consumption, low insulin levels or ketogenic diets. Ketogenic diets are commonly indicated as a therapy for treating central nervous system disorders, including Parkinson´s and Alzheimer´s disease, amyotrophic lateral sclerosis, refractory epilepsy and schizophrenia. However, the actions of ketone bodies on neurotransmission have been poorly explored and the mechanisms responsible for the therapeutic benefits of ketogenic diets are under study.Recently, Pflanz et al. (2019) reported the effects of ketone bodies on a ionotropic GABA receptor, describing acetone as a positive modulator, and β-hydroxybutyrate as a negative modulator, of the GABAAα1β2γ2 receptor function. In order to analyze the effects of ketone bodies on GABAergic neurotransmission, and since subunit composition confers specific pharmacological properties to the GABAA receptor subtypes, we evaluated the sensitivity of different phasic and tonic GABAA receptors to acetone. Human GABAA receptors were expressed in Xenopus laevis oocytes and chloride currents recorded by two-electrode voltage-clamp. Bath applications of acetone were performed at the plateau of GABA-evoked responses. Acetone inhibited GABAAρ1 and potentiated GABAAα1β2, GABAAα5β3 and GABAAα4β3δ receptor responses. Effects depended on both acetone and GABA concentration and were completely reversed after washout. Docking experiments with acetone are being carried out in order to identify the interaction sites.