negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of an adenylate cyclase-activating G protein-coupled receptor signaling pathway. [GOC:hjd, PMID:19246489]

Negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway involves a complex interplay of molecular mechanisms that dampen or suppress the activity of this crucial signaling cascade. This pathway is initiated when an extracellular ligand binds to a G protein-coupled receptor (GPCR), leading to activation of the receptor and subsequent activation of a heterotrimeric G protein. The activated G protein, specifically the Gα subunit, then stimulates adenylate cyclase, an enzyme that converts ATP into cyclic AMP (cAMP), a second messenger molecule that triggers downstream signaling events.

To effectively regulate this pathway and maintain cellular homeostasis, various mechanisms are employed to dampen or suppress its activity. These include:

1. **Desensitization of the receptor:** Upon prolonged stimulation, GPCRs undergo desensitization, a process that reduces their responsiveness to further ligand binding. This is achieved through phosphorylation of the receptor by specific kinases, such as GRKs (G protein-coupled receptor kinases), leading to the recruitment of arrestins, proteins that bind to the phosphorylated receptor and prevent its interaction with G proteins.

2. **Inhibition of G protein activation:** Inhibitory G proteins (Gi) can counteract the stimulatory effects of Gs proteins by competing for the same adenylate cyclase molecule or by directly interacting with the receptor and blocking its activation.

3. **Hydrolysis of cAMP:** cAMP phosphodiesterases (PDEs) catalyze the breakdown of cAMP, reducing its intracellular concentration and attenuating downstream signaling.

4. **Inhibition of effector enzymes:** Proteins like phosphodiesterases and protein kinases can directly inhibit downstream effectors, such as protein kinases, that are activated by cAMP.

5. **Activation of inhibitory pathways:** Other signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K) pathway, can be activated by upstream signals and lead to the inhibition of the adenylate cyclase-activating GPCR signaling pathway.

6. **Feedback loops:** Negative feedback loops are frequently employed to maintain the balance of signaling. For example, cAMP itself can activate protein kinases that phosphorylate and inhibit the receptor or adenylate cyclase, creating a self-regulatory mechanism.

These intricate regulatory mechanisms ensure that the adenylate cyclase-activating GPCR signaling pathway remains tightly controlled, preventing excessive or inappropriate activation that could lead to cellular dysfunction. The coordinated actions of these various mechanisms contribute to the fine-tuning and precise modulation of this critical signaling pathway, maintaining cellular homeostasis and regulating a wide range of physiological processes.'
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Proteins (7)

Compounds (159)