22.6
Voies de la Protéine Kinase Dépendantes de l'AMPc
L'adénosine monophosphate cyclique (AMPc) est un deuxième messager essentiel qui active la protéine kinase A (PKA) et régule divers processus biologiq…
Les ligands extracellulaires ou premiers messagers ne peuvent pas pénétrer directement dans les cellules. Au lieu de cela, ils se lient aux RCPG pour stimuler les protéines G, qui activent des enzymes telles que l’adénylyl cyclase libérant de grandes quantités du deuxième messager, l’AMP cyclique.
L’AMP cyclique transmet et amplifie des signaux principalement en activant la protéine kinase A ou PKA.
La liaison d’une molécule d’AMP cyclique aide davantage d’AMP cycliques à se lier aux sous-unités régulatrices de la PKA. Le changement conformationnel qui en résulte libère des sous-unités catalytiques PKA.
La PKA activée phosphoryle rapidement les protéines cibles cytosoliques, telles que la phosphorylase kinase et la glycogène synthase, en les activant ou en les inhibant. Cela empêche la conversion du glucose en glycogène et mobilise le glucose dans le corps.
La PKA activée pénètre également dans le noyau et phosphoryle la protéine cyclique de liaison aux éléments de réponse AMP ou CREB.
Le CREB phosphorylé se lie à l’élément de réponse cyclique AMP, ou CRE, sur les gènes cibles et initie la transcription des enzymes pour la synthèse du glucose, rétablissant ainsi les niveaux de glucose.
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Q1: How does cyclic AMP activate protein kinase A?
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.
Q2: What role does PKA play in glucose mobilization?
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.
Q3: How does signal amplification occur in the cAMP pathway?
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.
Q4: How does PKA regulate gene transcription in response to cAMP?
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.
Q5: Why does PKA produce different cellular responses in different cell types?
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.
Q6: How is the cAMP-PKA pathway turned off?
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.
Q7: What is the function of phosphoprotein phosphatase in the cAMP pathway?
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.