Direct energy consumption by inhibitory GABA _A receptors: from synaptic mechanisms to network activity

Despite the brain's use of adenosine triphosphate (ATP) to perform various intracellular processes, its major energy consumption occurs during neuronal communication. It is estimated that the majority of energy expenditure occurs at excitatory synapses via the activity of energy-dependent pumps (ATPases), which are involved in maintaining and restoring ion gradients after receptor activity. Inhibitory synapses are believed to contribute insignificantly to energy consumption because of their indirect energy consumption via cation-coupled chloride cotransporters (CCCs) and the subsequent function of Na⁺, K⁺ ATPase. Recent findings concerning the properties of inhibitory receptors suggest that they directly contribute to energy consumption. Fast synaptic inhibition in the brain is mediated by type A GABA _A receptors (GABA _A Rs), which are ligand-gated, anion-selective channels that are open upon the binding of the neurotransmitter and that play a key role in regulating neuronal excitation. Impairment of their function during network/seizure activity is accompanied by changes in the ionic and energy levels in neurons, the mechanisms of which remain largely unclear. Clarification of these processes is crucial for the treatment of neurodegenerative disorders that are linked with dysregulation of the inhibition/excitation (I/E) balance and energy deficiency. Recent evidence has shown the presence of an ATP-hydrolyzing site in the structure of GABA _A Rs, which is involved in network activity. We hypothesized that this ATPase activity can directly contribute to energy use. This hypothesis is supported by data indicating that γ-phosphate analogs targeting distinct ATP binding and hydrolysis stages can reduce the receptor function under certain conditions. Moreover, some GABA _A Rs assemblies have the capacity to participate in both the passive and active transport of Cl^- against the electrochemical gradient. Finally, under conditions of brain hypoxia or glucose deficiency syndrome, the function of inhibitory neurons is primarily impaired. Here, we explore the ATPase hypothesis that some GABA _A R subtypes may be directly involved in reducing the energy budget, and we present arguments for and against this theory while highlighting gaps in our knowledge of this neurobiological process.