Therapeutically leveraging GABA_A 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.

Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level

“…Another point is that immune cells have been shown to secrete acetylcholine, dopamine, and gamma-aminobutyric acid (GABA), which mediate immune signaling and play important immunomodulatory roles [ 45 , 46 , 47 , 48 ]. In this study, pretreatment with TUB significantly attenuated the reversal of morphine-induced CD11b surface expression decrease by TP5’s treatments ( Figure 7 ), suggesting a process in which nAchRs are also partially involved.…”

Ligand-Gated Ion Channels as Targets for Treatment and Management of Cancers

“…The transmembrane portion of the receptor consists of a pentameric topology/structure with a central pore for ion passage upon binding of the ligand ( Figure 1 ). We focus on the GABA A R due to its proposed role in cell proliferation which highlights it as a potential pro-cancerous ligand-gated ionotropic channel ( Takehara et al, 2007 ; Young and Bordey, 2009 ; Bhattacharya et al, 2021 ).…”

“…The most common adult human assembly is of a hetero-pentamer consisting of two α, two β, and one γ-subunit encoded by GABR genes GABRA , GABRB , and GABRG , respectively. The ligand (GABA) binding site is at the interface between α- and β-subunits ( Figure 4 ; Olsen, 2018 ; Bhattacharya et al, 2021 ). Normally, a GABA A R allows for the passage of chloride anions intracellularly through the transmembrane pentameric pore following the binding of GABA.…”

“…Another potential pathway by which GABAergic signaling can influence tumor cell death is by modulating cells of the immune system. GABA A Rs appear to have roles in many immune cell subtypes, including T-cells, dendritic cells, macrophages, and neutrophils ( Jin et al, 2013 ; Bhattacharya et al, 2021 ). Moreover, several immune cells have the capability of synthesizing and secreting GABA, including T-cells, macrophages, and dendritic cells ( Bhat et al, 2010 ; Dionisio et al, 2011 ).…”

Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations

“…Despite the fact that its central function is synaptic signaling, PLGICS are also expressed in non-neural cells where they play a diversity of roles, including stem cell and cancer proliferation ( Young and Bordey, 2009 ; Zhang et al, 2013 ; Bhattacharya et al, 2021 ). GlyR is no exception and is known to be expressed in cells as diverse as hepatocytes, spermatozoa, pancreatic, endothelial, or renal cells ( Lynch, 2004 ; Van den Eynden et al, 2009 ).…”