Functional Importance of Transient Receptor Potential (TRP) Channels in Neurological Disorders

Abstract

Transient receptor potential (TRP) channels are transmembrane protein complexes that play important roles in the physiology and pathophysiology of both the central nervous system (CNS) and the peripheral nerve system (PNS). TRP channels function as non-selective cation channels that are activated by several chemical, mechanical, and thermal stimuli as well as by pH, osmolarity, and several endogenous or exogenous ligands, second messengers, and signaling molecules. On the pathophysiological side, these channels have been shown to play essential roles in the reproductive system, kidney, pancreas, lung, bone, intestine, as well as in neuropathic pain in both the CNS and PNS. In this context, TRP channels have been implicated in several neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and epilepsy. Herein, we focus on the latest involvement of TRP channels, with a special emphasis on the recently identified functional roles of TRP channels in neurological disorders related to the disruption in calcium ion homeostasis.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; TRP channels; amyotrophic lateral sclerosis; calcium homeostasis; epilepsy; neurological disorders.

FIGURE 1

Schematic of the molecular mechanism of TRP channel-mediated pathogenesis of neurological disorders: (A) Alzheimer’s disease, (B) Parkinson’s disease, (C) Huntington’s disease, (D) Amyotrophic lateral sclerosis, and (E) epilepsy. In the figure, red arrows represent increase or up-regulation; green arrows, decrease or down-regulation; red thick bar, inhibition of the signaling pathway; and black arrows, activation of the signaling pathway. Ion channels involved in each of the neurological disorders and their transporting ions, channel agonists, and antagonists are also shown in the figure. Abbreviations: BDNF, brain-derived neurotrophic factor; ROS, reactive oxygen species; Aβ, beta-amyloid; PPAR, peroxisome proliferator-activated receptor gamma; AMPK, 5′ adenosine monophosphate-activated protein kinase; mTOR, mechanistic target of rapamycin; NMDAR, N-methyl-D-aspartate receptor; NAADP, Nicotinic acid adenine dinucleotide phosphate; PI(3,4)P₂, phosphatidylinositol (3,4)-bisphosphate; PD, Parkinson’s disease; ER, endoplasmic reticulum; GABA, gamma-aminobutyric acid; DA, dopamine; ALS/FTD, amyotrophic lateral sclerosis patients with frontotemporal dementia; L-BMAA, L-beta-methylamino-L-alanine; IL, interleukin; TNF-α, tumor necrosis factor alpha; CPZ, capsazepine; IRTX, 5′-Iodoresiniferatoxin; KA, kainic acid; pPKCα, phospho-protein kinase C alpha; pERK1/2, phospho-extracellular signal-regulated kinase 1/2.