Intracellular Signaling Pathways Activated by Endothelins

Occupation of the endothelin A receptor (ET_AR) induces activation of phospholipase C (PLC) which is central to the generation of cellular responses to endothelin 1 (ET-1). PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP₂) to form diacylglycerol (DAG) and D-myo-inositol-1,4,5-trisphosphate (IP₃). IP₃ regulates intracellular Ca²⁺ by binding to the IP₃ receptor on the endoplasmic reticulum (ER) and stimulating Ca²⁺ release from the ER stores. DAG binds to and activates protein kinase C (PKC). Increases in the concentration of intracellular Ca²⁺ is critical for eliciting responses to ETs. The ET_A receptor is linked to a Ca²⁺ channel (CaCh) in the plasma membrane that opens in response to receptor occupation by ET-1 or its agonists, thus further increasing the intracellular Ca²⁺content. ETs have also been shown to open nonselective cation channels (NsCh) or chloride channels (ClCh) to induce cellular depolarization by increasing in influx of Na⁺ and efflux of Cl^-, respectively. ETs also open potassium channels (KCh) which leads to the passive efflux of K⁺ and hyperpolarization that, in turn, inhibits the CaCh and Ca²⁺ influx.

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References:

Neylon, C.B, Vascular biology of endothelin signal transduction. Clin. Exp. Pharmacol. Physiol., 26, 149-153 (1999).

Masaki, T., et al., Subcellular mechanisms of endothelin action in vascular system. Eur. J. Pharmacol., 375, 133-138 (1999).