22.6
Vías de la proteína quinasa dependiente de AMPc
El monofosfato de adenosina cíclico (AMPc) es un segundo mensajero esencial que activa la proteína quinasa A (PKA) y regula diversos procesos biológic…
Los ligandos extracelulares o primeros mensajeros no pueden entrar directamente en las células. En su lugar, se unen a los GPCR para estimular las proteínas G, que activan enzimas como la adenilil ciclasa que liberan grandes cantidades del segundo mensajero, el AMP cíclico.
El AMP cíclico transmite y amplifica señales principalmente mediante la activación de la proteína quinasa A o PKA.
La unión de una molécula de AMP cíclico ayuda a que más AMP cíclicos se unan a las subunidades reguladoras de PKA. El cambio conformacional resultante libera subunidades catalíticas PKA.
La PKA activada fosforila rápidamente las proteínas diana citosólicas, como la fosforilasa quinasa y la glucógeno sintasa, activándolas o inhibiéndolas. Esto evita la conversión de glucosa en glucógeno y moviliza la glucosa en el cuerpo.
La PKA activada también entra en el núcleo y fosforila la proteína de unión al elemento de respuesta cíclica del AMP o CREB.
El CREB fosforilado se une al elemento de respuesta cíclico del AMP, o CRE, en los genes diana e inicia la transcripción de enzimas para la síntesis de glucosa, restaurando así los niveles de glucosa.
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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.