adrenomedullin receptor signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by an extracellular adrenomedullin combining with a dimeric adrenomedullin receptor on the surface of the target cell. [GOC:bhm, PMID:10882736]

Adrenomedullin (ADM) is a potent vasodilator peptide that plays a crucial role in regulating blood pressure, vascular tone, and inflammation. It exerts its effects through the adrenomedullin receptor (ADM-R), a G protein-coupled receptor (GPCR) that is expressed in various tissues, including vascular smooth muscle cells, endothelial cells, and cardiomyocytes. The signaling pathway initiated by ADM-R activation involves a complex cascade of molecular events:

1. **Ligand Binding:** ADM binds to its receptor, ADM-R, with high affinity, initiating the signaling cascade.
2. **G Protein Activation:** Upon ligand binding, ADM-R undergoes conformational changes that activate a heterotrimeric G protein, typically Gs. This activation leads to the dissociation of the Gα subunit from the Gβγ subunit.
3. **Adenylate Cyclase Activation:** The activated Gα subunit, specifically Gαs, interacts with and activates adenylate cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP).
4. **cAMP Production:** Activated adenylate cyclase catalyzes the production of cAMP, a second messenger molecule that plays a pivotal role in intracellular signaling.
5. **Protein Kinase A (PKA) Activation:** cAMP binds to and activates protein kinase A (PKA), a serine/threonine kinase.
6. **Phosphorylation of Target Proteins:** Activated PKA phosphorylates various downstream target proteins, including transcription factors, ion channels, and enzymes, leading to diverse cellular responses.
7. **Cellular Responses:** The phosphorylation events mediated by PKA trigger a variety of cellular responses, including:
- **Vasodilation:** ADM-R signaling promotes vasodilation by relaxing vascular smooth muscle cells, leading to decreased blood pressure.
- **Anti-inflammatory effects:** ADM-R activation inhibits the release of pro-inflammatory cytokines and chemokines, contributing to the resolution of inflammation.
- **Cardioprotective effects:** ADM-R signaling protects the heart from ischemia-reperfusion injury and promotes angiogenesis.
- **Cellular proliferation and differentiation:** ADM-R signaling can regulate cell growth and differentiation in certain cell types.

In addition to the canonical cAMP/PKA pathway, ADM-R signaling can also activate other signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the mitogen-activated protein kinase (MAPK) pathway, contributing to its pleiotropic effects. The specific downstream targets and signaling pathways activated by ADM-R depend on the cell type and the specific context.

Overall, the adrenomedullin receptor signaling pathway plays a crucial role in regulating vascular function, inflammation, and cardiovascular homeostasis. Dysregulation of this pathway has been implicated in various pathological conditions, including hypertension, atherosclerosis, and heart failure. Understanding the intricate mechanisms of ADM-R signaling is crucial for developing novel therapeutic strategies targeting this pathway for the treatment of these diseases.'
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Proteins (3)

Compounds (8)