The role of GIRK2 in regulating activity is enhanced with an unexpected link to metabolism. A recent study by Prytkova and colleagues found an intriguing interaction between ethanol treatment, neuronal excitability and metabolic performance of neurons (Prytkova et al., 2024). Overexpression of GIRK2 in iPSC-derived excitatory neurons, either by CRISPR activation (CRISPRa) or lentiviral expression, produced basal hyperpolarization of the neuronal membrane. Treatment of cultures with ethanol (17 mM for 14–21 days) enhanced firing of glutamatergic neurons but GIRK2 overexpression prevented this hyperexcitability. Finally, prolonged ethanol treatment induced metabolism-associated genes and resulted in a surge of mitochondrial respiration rates, which were reversed by overexpression of GIRK2. This study is the first to link neuronal responses to ethanol directly with changes in excitability and metabolic status of glutamatergic neurons. Taken together, these findings lead us to propose that ethanol, despite the fact it has many potential targets in neurons, may induce a generalized metabolic response, which serves as a constraint affecting key neuronal functions.
