response to endothelin

Definition

Target type: biologicalprocess

Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an endothelin stimulus. Endothelin is any of three secretory vasoconstrictive peptides (endothelin-1, -2, -3). [PMID:16365184]

Endothelin (ET) is a potent vasoconstrictor peptide that plays a critical role in regulating vascular tone, blood pressure, and cardiovascular homeostasis. Its biological effects are mediated through the activation of two G protein-coupled receptors, ETA and ETB, which are expressed in various tissues, including vascular smooth muscle cells, endothelial cells, and the heart.

Upon binding of endothelin to its receptor, a series of intracellular signaling events are triggered, leading to diverse cellular responses. These responses are highly context-dependent and vary based on the cell type, receptor subtype, and downstream signaling pathways involved.

**Signal Transduction Pathways:**

1. **Gq/11 protein activation:** Binding of endothelin to ETA or ETB receptors activates the Gq/11 protein, leading to the activation of phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3).

2. **Calcium mobilization:** IP3 diffuses to the endoplasmic reticulum (ER) and binds to IP3 receptors, triggering the release of intracellular calcium. The increased calcium levels activate downstream signaling pathways, including the calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC).

3. **Activation of MAP kinases:** DAG activates PKC, which in turn can activate various downstream signaling cascades, including the mitogen-activated protein kinases (MAPKs). MAPKs, such as ERK1/2, p38 MAPK, and JNK, play important roles in cell proliferation, differentiation, and apoptosis.

**Cellular Responses:**

**Vasoconstriction:**
- Activation of ETA receptors in vascular smooth muscle cells triggers a cascade of events leading to vasoconstriction.
- This involves calcium influx, myosin light chain phosphorylation, and increased contractility.
- ET-induced vasoconstriction plays a significant role in regulating blood pressure and maintaining vascular tone.

**Endothelial Cell Function:**
- Endothelial cells express both ETA and ETB receptors.
- Activation of ETB receptors in endothelial cells promotes the release of nitric oxide (NO), a potent vasodilator.
- This paradoxical response contributes to the complex regulation of vascular tone by endothelin.

**Cardiovascular Remodeling:**
- Prolonged exposure to endothelin can lead to cardiovascular remodeling, characterized by thickening of the heart muscle, changes in blood vessel structure, and increased fibrosis.
- This effect is attributed to the activation of signaling pathways involved in cell proliferation, migration, and extracellular matrix deposition.

**Other Biological Processes:**
- Endothelin is implicated in a wide range of other biological processes, including wound healing, inflammation, and neurotransmission.
- Its roles in these processes are still being investigated, but likely involve the activation of various signaling pathways and downstream effects.

**Regulation and Pathological Roles:**

- Endothelin production is tightly regulated by various factors, including shear stress, hypoxia, and inflammatory mediators.
- Imbalances in endothelin signaling are associated with various cardiovascular diseases, including hypertension, atherosclerosis, and heart failure.
- In these conditions, increased endothelin levels contribute to vasoconstriction, inflammation, and vascular remodeling, promoting disease progression.

**Therapeutic Implications:**

- The involvement of endothelin in cardiovascular disease has prompted the development of endothelin receptor antagonists, which are used to treat hypertension and pulmonary arterial hypertension.
- These drugs effectively block the actions of endothelin, promoting vasodilation and reducing disease-related complications.

**Conclusion:**

Endothelin signaling plays a multifaceted role in regulating various biological processes, particularly in the cardiovascular system. Understanding the complex interplay between endothelin receptors, signaling pathways, and cellular responses is crucial for developing targeted therapies to treat cardiovascular diseases and other endothelin-related conditions.'
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Proteins (1)

Compounds (41)