Figure 1.

A model for excitation/contraction coupling in a tonic smooth muscle cell in which sustained contraction involves Ca²⁺ entry through both VOCCs and SOCCs. (1) Physiologically, SOCE is initiated either by stimulation of receptors that couple through heterotrimeric GTP-binding protein (G proteins) to activate phospholipase C_β (PLC_β) or (2) by stimulation of receptors that couple through tyrosine phosphorylation to activate PLCγ (Parekh and Penner, 1997; Patterson et al., 2002). This results in breakdown of phosphoinositide and production of IP₃. (3) This second messenger activates IP₃ receptors, which are ligand-gated Ca²⁺ channels located in the SR. The resulting release of Ca²⁺ into the cytoplasm causes a transient increase in [Ca²⁺]_i, whereas (4) emptying of Ca²⁺ stores generates a retrograde signal that activates SOCCs in the plasma membrane, which are responsible for the sustained increase in [Ca²⁺]_i after the initial Ca²⁺ transient. (5) Depleted Ca²⁺ stores generate a key messenger molecule called Ca²⁺ influx factor (CIF), which diffuses to the plasma membrane. (6) A cascade of plasma-membrane-delimited reactions in which (7) CIF displaces inhibitory CaM from the membrane-bound iPLA₂, leading to iPLA₂ activation and the generation of lysophospholipids (8) that in turn activate SOCCs. Ca²⁺ release from the SR causes the sensor (i.e., Ca²⁺-sensing STIM1 protein) to aggregate in areas close to the plasma membrane and to interact with SOCC (i.e., Orai1), which is believed to be the store-operated channel (9). On the other hand, (10) SOCC may also provide direct depolarization, independently of Ca²⁺ -activated Cl⁻ channel VOCCs are opened by membrane depolarization due to initial Ca²⁺ -release from SR, which stimulates a Ca²⁺ -activated Cl⁻ channel (11). (12) The plasma membrane NCX is involved in the regulation of Ca²⁺ homeostasis in blood vessels by contributing to Ca²⁺ entry. Finally, (13) NO/cGMP inhibits SOCCs, possibly by enhanced re-filling of the Ca²⁺ -stores. (14) Ca²⁺ sensitization might occur via agonist-induced activation of either the small G protein RhoA/Rho-associated kinase (Rho K) pathway or protein kinase C (PKC). A, agonist; CICR, Ca²⁺ -induced Ca²⁺ release; CIF, calcium influx factor; CLCA, Ca²⁺-activated Cl⁻ channel; iPLA₂, Ca²⁺-independent phospholipase A2; CaM, calmodulin; CPA, cyclopiazonic acid; DAG, diacylglycerol; G, GTP binding proteins; cGMP, guanosine-3′,5′-cyclicmonophosphate; IP₃, inositol-1,4,5-trisphosphate; NCX, Na⁺/Ca²⁺ exchanger; NO, nitric oxide; PKC, protein kinase C; PLC, phospholipase C; R, receptor; S, putative Ca²⁺ sensor; SOCC, store-operated Ca²⁺ channel; STIM1, stromal-interacting molecule 1; TG, thapsigorgin; TK, tyrosine kinase; V_m, membrane potential; VOCC; voltage-operated Ca²⁺ channel.