Fig. 2.

Ca²⁺ mobilization and Ca²⁺ removal mechanisms in VSM. Agonist (A)-receptor (R) interaction causes Ca²⁺ release from sarcoplasmic reticulum (SR) in response to 1,4,5-inositol trisphosphate (IP₃) and to Ca²⁺ via Ca²⁺-induced Ca²⁺ release (CICR). VSMC activation also stimulates Ca²⁺ influx through nonspecific Ca²⁺ leak, voltage-dependent Ca²⁺ channels (VDCC), receptor-operated channels (ROC), transient receptor potential (TRP) channels, and stretch-activated channels. Depletion of intracellular Ca²⁺ stores in SR causes the release of stromal interaction molecule (STIM1) which in turn stimulates Orai1 store-operated Ca²⁺ channels. The increased intracellular Ca²⁺ is taken up by SR Ca²⁺-ATPase (SERCA) or extruded by the plasmalemmal Ca²⁺-ATPase (PMCA) or Na⁺-Ca²⁺ exchanger (NCX), and the resulting excess Na⁺ is extruded via Na⁺/K⁺ pump and Na⁺/H⁺ exchanger. At very high and pathological increases in intracellular Ca²⁺, the mitochondria play a role in Ca²⁺ uptake and homeostasis. When Ca²⁺ is taken up by mitochondria, HPO₄²⁻ is also taken up via HPO₄²⁻:2OH⁻ exchange and calcium phosphate is formed. Under favorable conditions and when Ca²⁺ can be handled by SERCA, PMCA and NCX, mitochondrial Ca²⁺ is slowly released via a Ca²⁺ efflux pathway involving a Ca²⁺:2H⁺ or Ca²⁺:2Na⁺ antiporter. PIP₂, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; DAG, diacyglycerol