Gamma-Aminobutyric Acid Signaling in Damage Response, Metabolism, and Disease

Abstract

Gamma-aminobutyric acid (GABA) plays a crucial role in signal transduction and can function as a neurotransmitter. Although many studies have been conducted on GABA in brain biology, the cellular function and physiological relevance of GABA in other metabolic organs remain unclear. Here, we will discuss recent advances in understanding GABA metabolism with a focus on its biosynthesis and cellular functions in other organs. The mechanisms of GABA in liver biology and disease have revealed new ways to link the biosynthesis of GABA to its cellular function. By reviewing what is known about the distinct effects of GABA and GABA-mediated metabolites in physiological pathways, we provide a framework for understanding newly identified targets regulating the damage response, with implications for ameliorating metabolic diseases. With this review, we suggest that further research is necessary to develop GABA's beneficial and toxic effects on metabolic disease progression.

Keywords: cancer; gamma-aminobutyric acid; liver disease; metabolite; neurotransmitter.

Figure 1

The role of GABA and glutamate as neurotransmitters. In the early stages of cortical neurogenesis, glutamate and GABA depolarize cells in the ventricular region of the mouse embryo neocortex (left panel). Glutamate binds its receptor, which is known as N-methyl-D-aspartate receptor (NMDA receptor or NMDAR), to depolarize the neuron. Glutamate selectively interacts with α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and GABA can bind to gamma amino butyric acid (GABA)-B receptors. GABA and glutamate increase the concentration of Ca²⁺ in ventricular zone cells, and decrease DNA synthesis by activating voltage-gated Ca²⁺ channels. Although most metabolites regulate depolarization of the synapse, GABA-B involves hyperpolarization (right panel). GABA-B receptor activates potassium outflow channels through G-protein signaling to induce hyperpolarization. GABA-B receptor activates phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and anti-apoptotic factors to relieve oxidative stress.

Figure 2

The function of GABA in various organs. Schematic representation of gamma-aminobutyric acid (GABA) on transmission in the pancreas, skeletal muscle, adipose tissue, and liver. GABA induces hyperpolarization in alpha cells in the Islets of Langerhans in the pancreas by increasing the inflow of Cl⁻. The membrane hyperpolarization inhibits the action of glucagon secretion. GABA regulates glycemia by inhibiting alpha-cell function. On the other hand, GABA induces depolarization in beta cells in the Islets of Langerhans in the pancreas, skeletal muscle, adipocyte, and liver cells, by increasing the inflow of Ca²⁺. In this case, GABA activates the PI3K-AKT pathway to increase insulin sensitivity by upregulating glucose transporter 4 (GLUT4) expression.

Figure 3

GABA and fatty acid metabolism reduce the symptoms of liver disease. Schematic representation of dysfunction of lipid metabolism, which is linked to non-alcoholic fatty liver disease (NAFLD, NAFL). Growth differentiation factor 15 (GDF15) activates 5′-AMP-activated protein linase (AMPK) pathway to increase fatty acid oxidation (FAO, b-oxidation), which directly affects the accumulation of fatty acid in non-alcoholic steatohepatitis (NASH). Activation of FAO decreases oxidative stress and DNA damage in NASH and NAFL to a healthy liver. Moreover, GABA transaminase (GABA-T) converts alpha-ketoglutarate (a-KG) to gamma-aminobutyric acid (GABA), suggesting GABA directly regulates membrane potential in liver. Lipid accumulation in liver disease induces hepatocyte membrane depolarization and increases GABA outflow, which leads to hyperinsulinemia and aggravates the symptoms of NASH and NAFL.

Figure 4

GABA biosynthesis and catabolism. The major biosynthesis pathway of gamma-aminobutyric acid (GABA) from glutamine and alpha-ketoglutarate (a-KG). Glutaminase catalyzes the reaction of transforming glutamine to glutamate. The reverse reaction is controlled by glutamine synthase. Glutamate dehydrogenase (GDH) transforms glutamate to a-KG. Glutamate decarboxylase (GAD) catalyzes the reaction of transforming glutamate to GABA. GABA transaminase converts GABA to succinate semialdehyde. Succinic semialdehyde dehydrogenase (SSADH) catalyzes the reaction of transforming succinate semialdehyde (SSA) to succinic acid.