Contribution of TRPC Channels in Neuronal Excitotoxicity Associated With Neurodegenerative Disease and Ischemic Stroke

Abstract

The seven canonical members of transient receptor potential (TRPC) proteins form cation channels that evoke membrane depolarization and intracellular calcium concentration ([Ca2+]i) rise, which are not only important for regulating cell function but their deregulation can also lead to cell damage. Recent studies have implicated complex roles of TRPC channels in neurodegenerative diseases including ischemic stroke. Brain ischemia reduces oxygen and glucose supply to neurons, i.e., Oxygen and Glucose Deprivation (OGD), resulting in [Ca2+]i elevation, ion dyshomeostasis, and excitotoxicity, which are also common in many forms of neurodegenerative diseases. Although ionotropic glutamate receptors, e.g., N-methyl-D-aspartate receptors, are well established to play roles in excitotoxicity, the contribution of metabotropic glutamate receptors and their downstream effectors, i.e., TRPC channels, should not be neglected. Here, we summarize the current findings about contributions of TRPC channels in neurodegenerative diseases, with a focus on OGD-induced neuronal death and rodent models of cerebral ischemia/reperfusion. TRPC channels play both detrimental and protective roles to neurodegeneration depending on the TRPC subtype and specific pathological conditions involved. When illustrated the mechanisms by which TRPC channels are involved in neuronal survival or death seem differ greatly, implicating diverse and complex regulation. We provide our own data showing that TRPC1/C4/C5, especially TRPC4, may be generally detrimental in OGD and cerebral ischemia/reperfusion. We propose that although TRPC channels significantly contribute to ischemic neuronal death, detailed mechanisms and specific roles of TRPC subtypes in brain injury at different stages of ischemia/reperfusion and in different brain regions need to be carefully and systematically investigated.

TRPC channels as emerging targets for seizure disorders

“…Congenital deficiency in TRPC1/C4/C5 or TRPC4 alone in mice decreases the oxygen-glucose deprivation (OGD)-induced cell death of cultured cortical neurons and attenuates cerebral ischemic damage indicated by infarction and neurological deficits after transient middle cerebral artery occlusion [26]. These results demonstrate that the activation of TRPC1/C4/C5, especially TRPC4, might be required for the hypoxic-ischemic brain injury.…”

“…depolarization and elevation of cytosolic Ca 2+ concentration, both of which crucially regulate the cellular functions [24]. In the CNS, TRPC channels have been implicated in diverse neuronal functions, such as excitability, neurogenesis, and neurite outgrowth [24], as well as in excitotoxicity, apoptotic and necrotic cell death associated with ischemia-reperfusion injuries, and neurodegeneration [25,26]. Despite similarities of their roles in intracellular signal transduction, TRPC subfamily members may be involved in many distinct physiological functions due to their different tissue and cell distributions.…”

TRP channels in health and disease at a glance

“…Loss of TRPC1, TRPC4 and TRPC5 has also been shown to cause synaptic depression (Schwarz et al, 2019). Activation of TRPC1, TRPC4 and TRPC5 produces detrimental effects in ischemic stroke (Jeon et al, 2020), whereas activation of TRPC6 produces beneficial effects in ischemic stroke (Shekhar et al, 2021). Deletion of Trpc5 or Trpc4 results in reduced innate fear in mice (Riccio et al, 2009(Riccio et al, , 2014.…”

miR-155-5p in Extracellular Vesicles Derived from Choroid Plexus Epithelial Cells Promotes Autophagy and Inflammation to Aggravate Ischemic Brain Injury in Mice

“…Importantly, sudden depletion of oxygen and glucose most likely induces neuroinflammation and cell death as well as secondary injury to the brain during cerebral ischemia/reperfusion (I/R) and hypoperfusion [ 3 ]. A growing body of evidence has revealed the involvement of multimodal pathophysiologies in the cerebral I/R process, resulting in diverse outcomes, such as energy depletion, oxidative stress, excitotoxicity, ion imbalance, and altered gene expression pattern-mediated brain damage and motor/cognitive dysfunctions [ 4 ]. Ischemic brain injury (IBI) is unique in that once ischemia begins, irreparable brain damage can occur within minutes to hours [ 5 ].…”