negative regulation of cAMP-mediated signaling

Definition

Target type: biologicalprocess

Any process which stops, prevents, or reduces the frequency, rate or extent of cAMP-mediated signaling. [GOC:jl]

Negative regulation of cAMP-mediated signaling is a critical cellular process that ensures appropriate and controlled responses to various stimuli. cAMP (cyclic adenosine monophosphate) is a ubiquitous second messenger that plays a crucial role in diverse cellular functions, including gene expression, cell growth, and metabolism. The cAMP signaling pathway is initiated by the activation of G protein-coupled receptors (GPCRs) by extracellular ligands. Ligand binding to GPCRs triggers a cascade of events involving the activation of adenylyl cyclase, an enzyme responsible for catalyzing the conversion of ATP to cAMP. Increased cAMP levels activate protein kinase A (PKA), a serine/threonine kinase that phosphorylates various downstream targets, leading to a multitude of cellular responses. To maintain cellular homeostasis and prevent excessive cAMP signaling, cells employ a variety of mechanisms to negatively regulate this pathway. These regulatory mechanisms encompass multiple levels, including:

**1. Regulation of GPCR activity:** GPCR desensitization and downregulation are crucial mechanisms for attenuating cAMP signaling. Desensitization involves phosphorylation of the activated GPCR by G protein-coupled receptor kinases (GRKs), leading to the recruitment of arrestin proteins. Arrestins bind to phosphorylated GPCRs, preventing further activation of G proteins and promoting internalization of the receptor. Downregulation involves the removal of GPCRs from the cell surface via endocytosis, decreasing the number of available receptors for ligand binding.

**2. Regulation of adenylyl cyclase activity:** Adenylyl cyclase activity can be regulated by multiple factors. One key mechanism involves the inhibitory G protein (Gi), which is activated by specific GPCRs. Gi inhibits adenylyl cyclase, reducing cAMP production. Furthermore, intracellular calcium levels can also regulate adenylyl cyclase activity, with high calcium levels often leading to inhibition.

**3. Regulation of cAMP degradation:** cAMP levels are tightly controlled by the enzyme phosphodiesterase (PDE), which catalyzes the hydrolysis of cAMP to inactive AMP. PDE activity can be regulated by various factors, including phosphorylation, protein-protein interactions, and second messengers like calcium.

**4. Regulation of PKA activity:** PKA activity can be regulated by several mechanisms, including: a) the binding of cAMP to regulatory subunits of PKA, which releases the catalytic subunits and activates their kinase activity. b) phosphorylation of PKA by other kinases, which can modulate its activity. c) interaction of PKA with scaffolding proteins, which can target PKA to specific subcellular locations.

**5. Regulation of downstream targets:** The cellular effects of cAMP signaling are mediated by the phosphorylation of downstream targets by PKA. These downstream targets include transcription factors, ion channels, and enzymes. The phosphorylation of these targets can either activate or inhibit their function, depending on the specific target.

**6. Negative feedback loops:** Many components of the cAMP signaling pathway are involved in negative feedback loops that help to dampen the signal. For example, PKA can phosphorylate and inhibit adenylyl cyclase, reducing cAMP production. Similarly, some downstream targets of PKA can inhibit the activity of GPCRs or adenylyl cyclase.

**In summary**, negative regulation of cAMP-mediated signaling is a complex and multifaceted process that involves multiple levels of control. These regulatory mechanisms ensure that cAMP signaling is appropriately balanced, preventing excessive or inappropriate activation of the pathway and maintaining cellular homeostasis. '"

Proteins (7)

Compounds (104)