Therapeutically leveraging GABAA receptors in cancer

Abstract

γ-aminobutyric acid or GABA is an amino acid that functionally acts as a neurotransmitter and is critical to neurotransmission. GABA is also a metabolite in the Krebs cycle. It is therefore unsurprising that GABA and its receptors are also present outside of the central nervous system, including in immune cells. This observation suggests that GABAergic signaling impacts events beyond brain function and possibly human health beyond neurological disorders. Indeed, GABA receptor subunits are expressed in pathological disease states, including in disparate cancers. The role that GABA and its receptors may play in cancer development and progression remains unclear. If, however, those cancers have functional GABA receptors that participate in GABAergic signaling, it raises an important question whether these signaling pathways might be targetable for therapeutic benefit. Herein we summarize the effects of modulating Type-A GABA receptor signaling in various cancers and highlight how Type-A GABA receptors could emerge as a novel therapeutic target in cancer.

Keywords: GABA; GABAA receptors; benzodiazepines; cancer; ion channels.

Figure 1.

Expression of Type-A GABA receptor subunit genes in normal human tissues. Genes coding for subunits of Type-A GABA receptor, GABR genes, has been observed in the CNS and from many systemic sources (left). Expression of GABR genes has also been reported in various cells of the immune system (right). In many of these tissues and cells, Type-A GABA receptor activity has been reported and connected to function.

Figure 2.

Type-A GABA receptor function-structure. (a) Type-A GABA receptor is a pentameric assembly with five transmembrane subunits that form a ligand-gated ion channel. Shown are binding sites for two GABA ligands (yellow spheres) and benzodiazepine (red sphere). (b) Type-A GABA receptors function to move chloride anions across the cell membrane in response to the binding of its ligand (agonist) GABA. Benzodiazepines are positive allosteric modulators of the receptors and so act to enhance movement of chloride anions when GABA is bound to the receptor.

Figure 3.

Expression of Type-A GABA receptor subunit genes in the pediatric brain cancer medulloblastoma. Shown is a heatmap across four molecular subgroups of medulloblastoma (Top row: WNT, SHH, Group 3, and Group 4) and subtypes within each subgroup (lower row), where color scaling indicates low (green) to high (red) expression. In Group 3 patient tumors (yellow), there is enhanced expression of GABRA5, which codes for the α-5 subunit. In contrast, in WNT patient tumors (blue), there is enhanced expression of a different set of GABR genes. While in SHH patient tumors (red) there is a subset of patients (purple) that share an enhanced expression of yet a different set of GABR genes. Figure adapted from Kallay, et al. Modulating native GABAA receptors in medulloblastoma with positive allosteric benzodiazepine-derivatives induces cell death. J Neurooncol 2019;142:411–422.

Figure 4.

Model of the mechanism of benzodiazepine-mediated cell death. (1) Binding of GABA (agonist) to a Type-A GABA receptor (GABA_AR) “opens” the channel to allow flow of chloride anions out of a cancer cell. This efflux of chloride anions is reflective of the depolarizing nature of the GABA_AR in embryonal cells. (2) Benzodiazepines (positive allosteric modulators of the receptor) enhance the chloride efflux. (3) The significant movement of chloride anions contributes to depolarizing of the mitochondria in the cancer cell and induces mitochondrial fission. This may contribute to mitochondrial dysfunction such as release of reactive oxygen and/or nitrogen, as well as impact ATP production. (4) The p53 signaling pathway is activated in these cancer cells in response to perturbation in ion homeostasis. (5) In addition, the intrinsic (mitochondrial) apoptotic pathway is triggered with an associated role for the pro-apoptotic protein BAD, BCL2 associated agonist of death. (6) In addition to binding to resident GABA_AR on cancer cells, benzodiazepine binds to the GABA_AR on immune cells. This event may contribute to enhanced infiltration of polyfunctional CD8+ T cells and macrophage phagocytosis.