TRP channels: Role in neurodegenerative diseases and therapeutic targets

Abstract

TRP (Transient receptor potential) channels are integral membrane proteins consisting of a superfamily of cation channels that allow permeability of both monovalent and divalent cations. TRP channels are subdivided into six subfamilies: TRPC, TRPV, TRPM, TRPP, TRPML, and TRPA, and are expressed in almost every cell and tissue. TRPs play an instrumental role in the regulation of various physiological processes. TRP channels are extensively represented in brain tissues and are present in both prokaryotes and eukaryotes, exhibiting responses to several mechanisms, including physical, chemical, and thermal stimuli. TRP channels are involved in the perturbation of Ca²⁺ homeostasis in intracellular calcium stores, both in neuronal and non-neuronal cells, and its discrepancy leads to several neuronal disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). TRPs participate in neurite outgrowth, receptor signaling, and excitotoxic cell death in the central nervous system. Understanding the mechanism of TRP channels in neurodegenerative diseases may extend to developing novel therapies. Thus, this review articulates TRP channels' physiological and pathological role in exploring new therapeutic interventions in neurodegenerative diseases.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Ca2+ homeostasis; Huntington's disease; Parkinson's disease; TRP.

Fig. 1

Role of TRP channels in Alzheimer's disease. Aβ-peptide stimulates the TRPA1 and enhances the ROS generation, which destabilizes the intracellular Ca2+ homeostasis, and initiation of IP3R initiates ER Ca2+ store depletion, resulting in the elevation of cytoplasmic Ca2+ which increases the expression of PP2B and NFкB. Generation of ROS, released in the cytosol, can trigger TRPM2 and a subsequent increase in intracellular Ca2+ ions induce NO production. Activated astrocytes and microglial cells by Aβ promotes TNFα, activating TRPM2 and NO, which stimulates TRPC5 and mediates Ca2+-dependent NO production by neuronal NOS. Aβ triggers the activation of neuroinflammatory processes, directed by activated-glial cells that produce inflammatory cytokines, which activate TRPV1. All these events cause neuronal death and eventually lead to the pathogenesis of AD.

Fig. 2

Role of TRP channels in Parkinson's disease. PD causes the stimulation of TRPV1, TRPC1, and TRPC3 channels, as well as upregulates ROS formation. Initiation of TRPC1 triggers mitochondrial dysfunction. Inhibition of TRPV1 results in PD and upregulates ROS formation and inflammatory process. Initiation of TRP channels augments the intracellular Ca2+ levels, inflammatory response, and mitochondrial dysfunction, which eventually triggers the apoptotic cascade activation and neuronal loss in PD.

Fig. 3

Role of TRP channels in Huntington's disease. HD leads to the stimulation of TRPC1 and TRPC5 channels and increases the generation of ROS via the influx of cations into the cell. Kir4.1 channel alters the K+ homeostasis and activates striatal astrocytes in mHTT protein, which causes hyperexcitability in neurons. Alteration in Ca2+ homeostasis leads to mitochondrial dysfunction and loss of synapsis in MSNs. TRPC1 and TRPC5 account for the excess influx of Ca2+ ions involved in Ca2+-dependent apoptosis in the striatum, which causes striatal neuronal loss and ultimately leads to HD.

Fig. 4

Role of TRP channels in Amyotrophic lateral sclerosis. In ALS, activation of voltage-gated Na + ion channels and decreased conduction of K+ ions causes hyperexcitability of axons. ROS generation causes SOD1 dysfunction, which disrupts the VDAC1 and causes mitochondrial-dependent apoptosis, and alteration in the Mg2+ ion homeostasis contributes to the etiology of ALS.