Cardiovascular Mitochondrial Dysfunction Induced by Cocaine: Biomarkers and Possible Beneficial Effects of Modulators of Oxidative Stress

Figure 1

Main players of the cell Ca²⁺ molecular machinery as putative cocaine targets. Ideal intracellular Ca²⁺ concentration is maintained through complex equilibria among the extracellular space (1 mM), the cytoplasm (0.1 μM), and the cellular stores (1.0–10 μM), such as the mitochondrion, the endoplasmic reticulum (ER), the Golgi apparatus, and nucleus. The ion trafficking occurs via a variety of selective membrane channels, Ca²⁺-binding proteins and transporters and ion exchangers and receptors, altogether responsible for Ca²⁺ import, export, and homeostasis. Import occurs at the level of (i) cell plasma membrane through the calcium release-activated Ca²⁺ channel protein 1 (ORAI1), the store-operated calcium entry channels (SOCE), and specific receptor-operated channels (ROC) such as AMPA, NMDA, TRPC, and the voltage-dependent calcium channels (VDCC); (ii) endoplasmic reticulum (ER) through the sarco/endoplasmic reticulum calcium ATPase (SERCA); (iii) mitochondria intermembrane space through the voltage-dependent anion channel (VDAC); and (v) in the matrix by the mitochondrial uniporter (MCU), in synergy with the mitochondrial calcium uptake (MICU) system. Extrusion occurs at the level of (i) cell plasma membrane mainly by the plasma membrane calcium ATPase (PMCA) and the sodium calcium exchangers (NCX) also potassium-dependent (NCKX) and (ii) the ER by the ryanodine (RYR) and the inositol 1,4,5-trisphosphate receptors (I P3R), as well as by the mitochondrial permeability transition pore (MPTP).