Figure 2.

Intracellular calcium (Ca²⁺) and pH (pH_i) signaling by activation of TRP and PMCA in healthy and diseased condition of the brain. (A) Normal physiological function of intracellular Ca²⁺ and pH_i homeostasis. The activation of TRP channels leads to Ca²⁺ influx into the cytosol. Increased Ca²⁺ levels are regulated by PMCA. The activation of PMCA can cause acidification. Acidification conditions are mediated by pH_i recovery functions regulated by NBC and NHE. (B) Neurodegenerative diseases caused by pathophysiological functions of intracellular Ca²⁺ and pH_i homeostasis. (1) The activation of TRP channels leads to excess Ca²⁺ influx and overload Ca²⁺ is maintained due to ATP2B2, oxidation, and age-related downregulation of PMCA: Ca²⁺-dependent cell death. (2) PMCA overexpression due to cytoplasmic Ca²⁺ overload cause persistent acidification from inhibition of the pH_i recovery mechanism by oxidative stress or cell death program: acidification dependent cell death. Ultimately, abnormal intracellular Ca²⁺ and pH_i levels impair neuronal function, resulting in neurodegenerative diseases. TRP, transient receptor potential; PMCA, plasma membrane Ca²⁺ ATPase; NBC, Na⁺/${\text{HCO}}_3^{-}$ cotransporters; NHE, Na⁺/H⁺ exchangers.