Pkc

Constriction

FIGURE 15-14 Intracellular signaling mechanisms activated by endothelins. Activation of PKC is known to stimulate the opening of the Ca2+ channel. Activation of phospholipase C is central to the generation of cellular responses to ET. An increase in the concentration of intracellular free Ca2+ is indispensable to eliciting responses to the endothelins. ET also stimulates a plasma membrane Ca2+ channel and induces an increase in the influx of extracellular Ca2+. Since endothelins have been shown to open a nonselective cation channel or chloride channel and to induce depolarization (dep), it is likely that the Ca2+ channel may also be opened by depolarization. Endothelins also open a K+ channel and induce hyperpolarization (hyperp). This inhibits the Ca2+ channel. An increase in the concentration of [Ca2+]; inhibits Ca2+ influx. Activation of PKC is known to stimulate the opening of the Ca2+ channel. Abbreviations: ETr, ET receptor; G, G protein; PLC, phospholipase C; PLD, phospholipase D; IP3, inositol triphosphate; DG, diaclyglycerol; PKC, protein kinase C; [Ca2+]i, concentration of intracellular free Ca2+; CaCh, calcium channel; CICh, chloride channel; NsCh, nonselective cation channel; KCh, K+ channel. Inositol trisphosphate stimulates the intracellular calcium pool to release Ca2+. Modifed with permission from Masaki, T. (1993). Endothelins: Homeo-static and compensatory actions in the circulatory and endocrine systems. Endocri. Rev. 14, 256-268.

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