cAMP and cGMP

What are the two key requirements for signal transduction?

Diffusion of small chemical messengers and protein-protein interactions.

What are second messengers?

Short-lived, small, non-protein, diffusible intracellular molecules that relay, mediate, and amplify signals within cells.

Examples of common second messengers

Cyclic nucleotides (cAMP, cGMP), Ca²⁺ ions, and membrane-derived lipids.

How do second messengers terminate their effect?

By degradation or removal, which ends the cellular response.

What is signal amplification?

One signal molecule can activate many downstream molecules, greatly increasing the response.

What do protein kinases do?

Add phosphate groups to target proteins to activate or inactivate them.

What do protein phosphatases do?

Remove phosphate groups from proteins, reversing kinase actions.

What type of molecule is cAMP?

A cyclic nucleotide derived from ATP, acting as a second messenger.

Which receptors use cAMP?

G-protein coupled receptors (GPCRs).

Which enzyme synthesizes cAMP?

Adenylate cyclase.

What activates adenylate cyclase?

Activated G-proteins (specifically Gα subunit).

What does cAMP do inside the cell?

Activates Protein Kinase A (PKA) and other effectors.

What is the structure of PKA?

A tetramer with two regulatory and two catalytic subunits.

How is PKA activated?

cAMP binds to regulatory subunits, releasing active catalytic subunits.

What type of kinase is PKA?

A serine/threonine kinase.

Main functions of PKA

Phosphorylates enzymes and transcription factors to regulate metabolism and gene expression.

Examples of PKA target enzymes

Lipase, glycogen phosphorylase, cholesterol esterase (activated); glycogen synthase (inhibited).

How does PKA regulate gene expression?

Phosphorylates CREB (cAMP Response Element Binding protein) to activate cAMP-responsive genes.

How is cAMP degraded?

By cyclic nucleotide phosphodiesterases (PDEs), converting cAMP into 5′-AMP.

What happens when cAMP is degraded?

Protein Kinase A activity decreases.

List steps that inactivate GPCR signaling

Signal dissociation, GTP hydrolysis, PDE activation, protein dephosphorylation, receptor desensitization.

What are two mechanisms of receptor desensitization?

PKA-mediated phosphorylation and β-arrestin–mediated internalization.

Describe β-arrestin–mediated desensitization

Phosphorylated GPCR binds β-arrestin, is endocytosed via clathrin, then dephosphorylated and recycled.

Examples of diseases linked to disrupted cAMP signaling

Cholera, pertussis, cataract, diabetes, cardiovascular diseases, cancer.

How does cholera toxin affect cAMP signaling?

Activates G-proteins, leading to excessive cAMP and water loss.

How does diabetes relate to cAMP?

Disrupted PKA affects insulin secretion.

What is cGMP?

A cyclic nucleotide formed from GTP that acts as a second messenger.

Which enzyme synthesizes cGMP?

Guanylate cyclase.

Which enzyme degrades cGMP?

cGMP phosphodiesterase (PDE).

Types of phosphodiesterases (PDEs)

cAMP-specific (PDE4,7,8), cGMP-specific (PDE5,6,9), dual (PDE1,2,3,10,11).

Two types of guanylate cyclase receptors

Soluble (activated by nitric oxide) and membrane-bound (activated by ANP, BNP).

What does cGMP regulate?

Ion channels, protein kinases (PKG), and phosphodiesterases.

What is PKG?

Protein Kinase G, a serine/threonine kinase activated by cGMP.

Functions of PKG

Regulates smooth muscle relaxation, platelet function, sperm metabolism, cell division.

Describe NO–cGMP signaling pathway

NO diffuses into cells → activates guanylate cyclase → increases cGMP → activates PKG → muscle relaxation.

Physiological outcome of NO–cGMP signaling

Smooth muscle relaxation and increased blood flow.

Medical relevance of cGMP signaling

Regulation of blood pressure, erectile function, and vascular health.

How does nitroglycerin work?

Releases NO, which activates cGMP to relax blood vessels and improve blood flow.

How does Viagra work?

Inhibits PDE5, preventing cGMP breakdown and prolonging smooth muscle relaxation.

Compare cAMP and cGMP signaling

Both activate kinases (PKA vs PKG), regulate enzymes and transcription, and are degraded by PDEs; differ in origin and physiological effects.