cAMP-abhängige Proteinkinasewege

Cyclic AMP binds to the regulatory subunits of PKA, causing a conformational change that releases the catalytic subunits. The binding of four cAMP molecules is required to fully dissociate the catalytic subunits from the regulatory subunit, activating PKA. Once activated, PKA rapidly phosphorylates downstream target proteins to generate cellular responses.

PKA phosphorylates and activates glycogen phosphorylase kinase, which then activates glycogen phosphorylase to break down glycogen into glucose. Simultaneously, PKA phosphorylates and inhibits glycogen synthase, preventing glycogen synthesis. PKA also phosphorylates an inhibitor of phosphoprotein phosphatase, blocking the enzyme from reversing these phosphorylations and maintaining glucose mobilization.

A single epinephrine molecule binds one GPCR and activates multiple heterotrimeric G proteins. Each G protein stimulates adenylyl cyclase, which synthesizes large numbers of cAMP molecules. This cascade amplifies the initial signal, allowing small changes in ligand concentration to produce large changes in cAMP levels and PKA activity.

Activated PKA enters the nucleus and phosphorylates CREB (cyclic AMP response element-binding protein). Phosphorylated CREB binds to CRE (cyclic AMP response element) sequences on target genes, initiating transcription of enzymes for glucose synthesis. This nuclear response restores glucose levels after the initial cytosolic mobilization phase.

PKA generates distinct responses by phosphorylating specific target proteins unique to each cell type. In liver and muscle cells, PKA activates glucose mobilization through glycogen breakdown. In adipose cells, PKA phosphorylates and activates lipase, breaking down triglycerides into free fatty acids. The same extracellular ligand triggers different outcomes based on available target proteins.

When the extracellular stimulus is removed, cAMP levels decrease, reducing PKA activation. Inactive PKA cannot phosphorylate the inhibitor of phosphoprotein phosphatase, allowing the phosphatase to become active. The phosphatase removes phosphates from glycogen-metabolizing enzymes, promoting glycogen synthesis and preventing further glucose mobilization.

Phosphoprotein phosphatase reverses PKA phosphorylation by removing phosphate groups from target enzymes. When active, it dephosphorylates glycogen phosphorylase kinase, glycogen phosphorylase, and glycogen synthase, switching the cell from glucose mobilization to glycogen synthesis. PKA controls phosphatase activity by phosphorylating its inhibitor protein.