The Role of TRP Channels and PMCA in Brain Disorders: Intracellular Calcium and pH Homeostasis

Abstract

Brain disorders include neurodegenerative diseases (NDs) with different conditions that primarily affect the neurons and glia in the brain. However, the risk factors and pathophysiological mechanisms of NDs have not been fully elucidated. Homeostasis of intracellular Ca2+ concentration and intracellular pH (pHi) is crucial for cell function. The regulatory processes of these ionic mechanisms may be absent or excessive in pathological conditions, leading to a loss of cell death in distinct regions of ND patients. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where disrupted Ca2+ homeostasis leads to cell death. The capability of TRP channels to restore or excite the cell through Ca2+ regulation depending on the level of plasma membrane Ca2+ ATPase (PMCA) activity is discussed in detail. As PMCA simultaneously affects intracellular Ca2+ regulation as well as pHi, TRP channels and PMCA thus play vital roles in modulating ionic homeostasis in various cell types or specific regions of the brain where the TRP channels and PMCA are expressed. For this reason, the dysfunction of TRP channels and/or PMCA under pathological conditions disrupts neuronal homeostasis due to abnormal Ca2+ and pH levels in the brain, resulting in various NDs. This review addresses the function of TRP channels and PMCA in controlling intracellular Ca2+ and pH, which may provide novel targets for treating NDs.

The mechanism of HMGB1 secretion and release

“…As a universal second messenger, calcium ions are involved in a wide range of cellular processes by exerting allosteric regulatory effects on intracellular enzymes or proteins 92 . The release of calcium ions and their transport between the cytoplasm and intracellular storage are regulated by numerous proteins, channels, and pumps 93 – 95 . Disrupted intracellular calcium signaling leads to severe cell damage and even cell death 96 – 98 .…”

Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development

“…Mammalian TRP channels comprise 28 members and are divided into six subfamilies based on sequence homology: canonical (TRPC), vanilloid (TRPV), ankyrin (TRPA), melastatin (TRPM), polycystin (TRPP), and mucolipin (TRPML) [ 1 , 2 , 3 ]. Most TRP channels belong to a large family group of non-selective and polymodal ion channels with diverse physiological functions and regulatory mechanisms and are implicated in different channelopathies [ 26 , 27 , 28 ]. TRPs are tetrameric channels formed by monomers with six transmembrane domains (S1–6) and cation-selective pores [ 26 , 29 , 30 ].…”

Análisis transcriptómico del remodelado de la homeostasis del calcio intracelular en cáncer de colon

“…Cabe destacar que este cáncer afecta de forma diferente a hombres que a mujeres, pues tanto la incidencia como mortalidad es superior en hombres. En particular, en 2020 el 55.19 % de los casos diagnosticados y el 55.14 % de muertes por CCR fue para los hombres, mientras que en España estos porcentajes fueron del 60.85 % y de 58.53 %, respectivamente (Sung et al (2021)). A pesar de que esta enfermedad era poco habitual en la década de los 50 del siglo XX, es obvio que ha escalado puestos en estos últimos 70 años, tanto en incidencia como en mortalidad.…”

“…No obstante, se han identificado alrededor de 30 variantes de splicing alternativo de estas bombas, muchas de ellas altamente especializadas, con un perfil de expresión específico de tejido y con funciones concretas. Por ejemplo, las isoformas 1 y 4 se expresan de forma ubicua en todos los tejidos, mientras que la 2 y la 3 son exclusivas de las neuronas del cerebro (Strehler and Zacharias (2001), Hwang et al (2021)).…”

“…Por lo tanto, las variantes de splicing ("a" y "b") que afectan a esta región tienen implicaciones en la regulación de estas bombas. De hecho, las proteínas que contienen dominios PDZ sólo pueden unirse a la variante de splicing "b" (Strehler and Zacharias (2001), Strehler (2013), Hwang et al (2021)).…”