Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

Figure 1

Intracellular calcium homeostasis. Intracellular calcium levels are tightly regulated within a narrow physiological range [23]. Cellular calcium influx through the plasma membrane is largely mediated by receptor-operated calcium channels (ROCC), voltage-operated calcium channels (VOCC), store-operated calcium channels (SOCC) and, under exceptional circumstances, the sodium/calcium exchanger (NCX). Under physiological conditions, NCX is mainly involved in calcium efflux; however it can also reverse its mode of operation (reverse mode exchange) thereby contributing to calcium influx, especially during strong depolarization and in the presence of high intracellular sodium concentrations [24]. Calcium may also be released into the cytoplasm from the endoplasmic reticulum, through inositol-1,4,5-trisphosphate (IP3R) and ryanodine receptors (RYR). Different systems operate within the cell to counterbalance the cytosolic calcium increase. Specifically, the plasma membrane calcium pump (PMCA), NCX, and sarcoendoplasmic reticulum calcium ATPase (SERCA) participate in restoring physiological calcium levels. The excess of intracellular calcium can also be taken up by mitochondria through the mitochondrial calcium uniporter (MCU). Calcium can be released back into the cytosol through the activity of mitochondrial NCX (mNCX), which can also reverse its mode of operation allowing the access of calcium ions into the mitochondrial matrix. Recently, the mitochondrial hydrogen/calcium exchanger (mHCX) has been proposed to be an electrogenic 1 : 1 mitochondrial calcium/hydrogen antiporter that drives the uptake of calcium into mitochondria at nanomolar cytosolic calcium concentrations [25]. PTP, permeability transition pore; MMCA, mitochondrial membrane Ca²⁺ATPase.