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

Abstract

Ligand-gated ion channels are an ionotropic receptor subtype characterized by the binding of an extracellular ligand, followed by the transient passage of ions through a transmembrane pore. Ligand-gated ion channels are commonly subcategorized into three superfamilies: purinoreceptors, glutamate receptors, and Cys-loop receptors. This classification is based on the differing topographical morphology of the receptors, which in turn confers functional differences. Ligand-gated ion channels have a diverse spatial and temporal expression which implicate them in key cellular processes. Given that the transcellular electrochemical gradient is finely tuned in eukaryotic cells, any disruption in this homeostasis can contribute to aberrancies, including altering the activity of pro-tumorigenic molecular pathways, such as the MAPK/ERK, RAS, and mTOR pathways. Ligand-gated ion channels therefore serve as a potential targetable system for cancer therapeutics. In this review, we analyze the role that each of the three ligand-gated ion channel superfamilies has concerning tumor proliferation and as a target for the treatment of cancer symptomatology.

GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiation-sensitize primary and brain-metastatic lung adenocarcinoma tumors

“…GABA(A) receptors also have roles outside of the CNS and receptor subunits are expressed in cancer cells. 19,20 We find in lung adenocarcinoma cells that GABA(A) receptors are functional and that their activation enhances the effect of its natural agonist, the metabolite GABA (Figure 1D). Previously, we found that activation of GABA(A) receptors in cancer cells contributes to an efflux of chloride anions.…”

“…GABA(A) receptors function as the major inhibitory neurotransmitter receptors and hyperpolarize post-synaptic mature neurons in response to the binding of its agonist, the metabolite GABA. We and others have reported on enhanced expression of GABA(A) receptor subunits in disparate cancers 19,20 and shown that GABA(A) receptors intrinsic to cancer cells are functional i.e., GABA responsive. Importantly, GABA(A) receptors in cancer cells are depolarizing, 21 which reflects an efflux of chloride anions like the embryonic receptor.…”

Ligand-Gated Ion Channels: Prognostic and Therapeutic Implications for Gliomas

“…The proposed link between ion influx and tumor growth is that intracellular Ca + mediates the activation of several pro-proliferative signal transduction pathways, such as Akt, ERK/MAP kinase, and PKA [ 11 , 12 ]. In addition to amino acid synthesis, glutamate is critical for the maintenance of homeostasis within the nervous system, providing significant excitatory innervation within the cortex [ 10 , 13 ]. Furthermore, glutamate is a precursor for glutathione, which may contribute to tumor pathogenesis as it is necessary for scavenging reactive oxygen species (ROS) [ 10 ].…”

“…In addition to amino acid synthesis, glutamate is critical for the maintenance of homeostasis within the nervous system, providing significant excitatory innervation within the cortex [ 10 , 13 ]. Furthermore, glutamate is a precursor for glutathione, which may contribute to tumor pathogenesis as it is necessary for scavenging reactive oxygen species (ROS) [ 10 ]. Stimulation of the glutamate receptor activates focal adhesion kinase (FAK), an enzyme responsible for the regulation of cell motility, growth, and invasion [ 4 ].…”

“…Serine and glycine are considered immunosuppressive metabolites and thus may contribute to the immune evasion of cancer cells [ 18 , 19 ]. Moreover, it has been suggested that GABA A may be implicated in cell proliferation, possibly impacting tumor pathogenesis [ 10 ]. For example, in breast cancer cells, increased expression of GABRA3 contributes to the activation of Akt, thereby enhancing proliferation via the Akt pathway [ 20 ].…”