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.
Highlights
Ionotropic receptors have a variety of triggering mechanisms, including ligand-gated, mechanosensitive, and chemosensitive
As with our discussion of other ligand-gated ionotropic receptors, we turn to recent developments in P2XR “antagonism” for tumor therapy
Microglia through intrathecal injection of bone marrow stromal cells attenuated neuropathic pain in a murine model (Ulmann et al, 2008; Teng et al, 2019). The mechanism of this nociception is thought to be activation of P2X4R on microglia by afferent neurons leading to MAPK signaling, which in turn leads to the synthesis and excretion of brain-derived neurotrophic factor (BDNF) (Ulmann et al, 2008; Trang et al, 2009)
Summary
Ionotropic receptors have a variety of triggering mechanisms, including ligand-gated, mechanosensitive, and chemosensitive. Ligand-gated ionotropic channel subtypes are commonly classified into one of three superfamilies: ATP-gated or purinoreceptors, glutamate-gated receptors, and Cys-loop receptors (Collingridge et al, 2009). These superfamily classifications are derived from the differing transmembrane domains of each superfamily, which in turn confer functional differences (Table 1). Ligand-gated ionotropic receptors are critical to maintaining a tightly controlled intracellular electrochemical balance in eukaryotic cells. As such, their disruption can lead to inappropriate activation of cellular pathways, including induction of a pro-tumorigenic phenotype. We detail the therapeutic potential to focally target the ligand-gated ionotropic channels and
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