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The mysterious role of protein kinase A: How does it affect our heartbeat and memory?
In the field of molecular biology, the cAMP-dependent pathway (also known as the adenylyl acylase pathway) is a signaling pathway triggered by G protein-coupled receptors, which plays a role in intercellular communication. important role. The discovery of cAMP dates back to the 1950s, revealed by Earl Sutherland and Ted Rall. With this discovery, cAMP was considered a secondary messenger, and calcium ions (Ca2+) also played a similar role. Sutherland won the 1971 Nobel Prize for discovering the mechanism of action of epinephrine in glycogenolysis, a process that requires cAMP as a secondary messenger.
When a G protein-coupled receptor is activated, it triggers a series of signal transduction events, ultimately affecting heart beating and memory formation.
Mechanism
G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins that respond to various extracellular stimuli. Each GPCR binds to a specific ligand and is activated. When a GPCR is activated by an external ligand, its conformation changes and signals are transmitted to attached intracellular hybrid G protein complexes. The Gsα subunit in the stimulated G protein complex will replace GDP with GTP and release it from the complex.
In the cAMP-dependent pathway, the activated Gsα subunit binds and activates an enzyme called adenylyl acylase, which in turn catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP). The increase in cAMP concentration may lead to the activation of multiple pathways, including heterocyclic nucleotide-gated ion channels and exchange proteins activated by cAMP (EPAC). In addition, the enzyme protein kinase A (PKA) is also cAMP-dependent and is only activated in the presence of cAMP.
PKA phosphorylates a variety of other proteins, leading to cardiac muscle contraction, conversion of glycogen to glucose, and regulation of gene expression.
Importance
In humans, cAMP works by activating protein kinase A (PKA). This enzyme is composed of two catalytic subunits and two regulatory subunits. The binding of cAMP to the regulatory subunits causes them to separate from the catalytic subunits. Subsequently, the catalytic subunit enters the nucleus and affects transcription. The cAMP-dependent pathway plays an important role in a variety of physiological processes, including increased heart rate, cortisol secretion, and breakdown of glycogen and fat. cAMP is essential for memory maintenance, heart relaxation, and kidney absorption of water.
Activation of the cAMP pathway will promote enzyme activation and regulation of gene expression. Rapid enzyme activation is in sharp contrast to slower gene expression regulation.
Research on this pathway is generally carried out by inhibiting or promoting cAMP function. If cAMP-dependent pathways are not controlled, it may ultimately lead to excessive cell proliferation, which may be associated with the development or progression of cancer.
Activation and deactivation
Activated GPCR triggers conformational changes in the attached G protein complex, causing the Gsα subunit to exchange GDP for GTP and dissociate from the β and γ subunits. Subsequently, the Gsα subunit activates adenylyl acylase, which rapidly converts ATP into cAMP, thereby activating the cAMP-dependent pathway. This pathway can also be further activated by direct activation of adenylyl acylase or PKA.
Molecules that activate the cAMP pathway include: cholera toxin (increases cAMP levels), forskolin (a natural compound that activates adenylyl acylase), caffeine, and theobromine (inhibits cAMP phosphodiesterase and reduces cAMP levels). degradation), and pertussis toxin, which increases insulin secretion.
Through these mechanisms, cAMP can play a key role in regulating the heart, metabolism, and brain memory.
When the Gsα subunit hydrolyzes GTP to GDP, the cAMP pathway is deactivated, possibly by directly inhibiting adenylyl acylase or dephosphorylating proteins phosphorylated by PKA. Molecules that inhibit the cAMP pathway include: cAMP phosphodiesterase (which converts cAMP to AMP, reducing cAMP levels), and Gi protein (which is a G protein that inhibits adenylyl acylase, reducing cAMP levels).
These research results make us realize that the biochemical processes hidden behind cell signaling not only affect the beating of the heart, but also involve our memory and learning. Does this make you reflect on how small changes in your daily life affect your physiology and emotions?
