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

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 (pH_i) 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 pH_i, 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.