endothelin receptor signaling pathway involved in heart process

Definition

Target type: biologicalprocess

An endothelin receptor signaling pathway which contributes to a circulatory system process carried out by the heart. [GOC:BHF, GOC:mtg_cardiac_conduct_nov11, PMID:17376402]

The endothelin receptor signaling pathway plays a critical role in regulating heart function, contributing to both normal physiology and pathological conditions. This pathway is activated by the binding of endothelin (ET) peptides, primarily endothelin-1 (ET-1), to G protein-coupled receptors (GPCRs) known as endothelin receptors (ETRs). There are three main ETR subtypes: ETA, ETB, and ETC.

**Signal Transduction:**

* **Ligand Binding:** ET-1 binds to ETRs, triggering a conformational change in the receptor.
* **G Protein Activation:** The activated receptor interacts with G proteins, specifically Gαq/11.
* **Phospholipase C (PLC) Activation:** Gαq/11 activates PLC, which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3).
* **Calcium Signaling:** IP3 binds to IP3 receptors on the endoplasmic reticulum (ER), releasing calcium ions (Ca2+) into the cytosol.
* **Protein Kinase C (PKC) Activation:** DAG activates PKC, a key signaling molecule.
* **MAP Kinase Activation:** The pathway further activates mitogen-activated protein kinases (MAPKs), including ERK, JNK, and p38, contributing to cell proliferation and gene expression.

**Cardiac Effects:**

* **Cardiomyocyte Contractility:** The pathway enhances myocardial contractility by increasing intracellular Ca2+ levels and activating PKC, which phosphorylates proteins involved in calcium handling and contractile machinery.
* **Cardiac Hypertrophy:** Chronic activation of the endothelin pathway promotes cardiac hypertrophy, a pathological enlargement of heart cells, by stimulating gene expression and protein synthesis through MAPK signaling.
* **Vascular Tone:** The pathway influences vascular tone, contributing to vasoconstriction through ETA receptor activation, and vasodilation through ETB receptor activation.
* **Cardiac Remodeling:** In response to stress or injury, the pathway participates in cardiac remodeling, a process that involves changes in heart structure and function.
* **Fibrosis:** The pathway contributes to cardiac fibrosis, the excessive deposition of collagen in the heart, by activating various downstream signaling pathways.

**Clinical Significance:**

The endothelin receptor signaling pathway is implicated in various cardiovascular diseases, including:

* **Hypertension:** The vasoconstrictive effects of endothelin contribute to high blood pressure.
* **Heart Failure:** Increased ET-1 levels are often observed in heart failure, contributing to cardiac remodeling and dysfunction.
* **Pulmonary Hypertension:** Endothelin plays a role in pulmonary hypertension, characterized by high blood pressure in the lungs.
* **Coronary Artery Disease:** The pathway is involved in the development of coronary artery disease, including atherosclerosis.

**Therapeutic Targets:**

The endothelin pathway has emerged as a promising therapeutic target for cardiovascular diseases. Several endothelin receptor antagonists have been developed, including bosentan, ambrisentan, and macitentan, which block the binding of ET-1 to its receptors. These drugs have shown efficacy in treating pulmonary hypertension and have the potential to be beneficial for other cardiovascular conditions.'
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Proteins (2)

Compounds (51)