Components of the adenylate cyclase system
The system includes integral and anchored membrane proteins, as well as cytosolic enzymes.
- Receptors ($R_s$ and $R_i$) are transmembrane proteins spanning the membrane seven times. On the extracellular side, they bind the primary messenger (hormone), and on the intracellular side, they interact with G proteins. They can move freely within the lipid bilayer (lateral diffusion).
- G proteins are GTP-binding heterotrimers consisting of three subunits: $\alpha$, $\beta$, and $\gamma$. In the inactive state, the $\alpha$-subunit holds a GDP molecule. There are stimulatory ($G_s$) and inhibitory ($G_i$) proteins.
- Adenylate cyclase (AC) is a membrane-bound effector enzyme that catalyzes the formation of the secondary messenger.
- Protein kinase A (PKA) is a cytosolic enzyme that directly executes the cellular response.
Mechanism of activation ($G_s$ pathway)
The process of stimulatory signal transduction involves a strict sequence of conformational changes:
- The hormone binds to the $R_s$ receptor, altering its spatial structure.
- The modified receptor acquires a high affinity for the inactive $G_s$ protein, forming a ternary complex on the membrane (hormone — receptor — $G_s$-GDP).
- This interaction causes the $\alpha_s$-subunit to release the GDP molecule and bind GTP.
- GTP binding alters the conformation of the $\alpha_s$-subunit: it detaches from the $\beta\gamma$ dimer and moves freely along the membrane.
- Upon reaching adenylate cyclase, the $\alpha_s$-GTP complex binds to its regulatory center and activates the enzyme.
- Adenylate cyclase begins converting ATP into the secondary messenger — cAMP, cleaving inorganic phosphate. The intracellular concentration of cAMP rises sharply.
Protein kinase A activation and cellular response
The accumulation of cAMP in the cytosol triggers the next step of the cascade. In the inactive state, protein kinase A is a $R_2C_2$ tetramer, where two regulatory subunits (R) block two catalytic subunits (C).
cAMP molecules bind to the regulatory subunits, causing them to lose their affinity for the catalytic parts. The complex dissociates, and the liberated C subunits gain enzymatic activity.
Active PKA phosphorylates intracellular target proteins at serine and threonine residues, consuming ATP. The attachment of the phosphate group acts as a "switch" that increases or decreases the activity of specific enzymes, thereby altering the rate of metabolic processes.
Regulation of gene expression
Hormones utilizing the adenylate cyclase pathway (e.g., glucagon, parathyroid hormone, vasopressin) can influence not only the activity of existing enzymes but also the synthesis of new ones.
Free catalytic subunits of PKA enter the cell nucleus, where they phosphorylate a specific transcription factor — CREB (cAMP response element-binding protein). Activated CREB-P acquires a high affinity for a regulatory DNA region — the CRE element.
Binding to DNA stimulates the expression of structural genes. This produces mRNA, and translation of specific proteins begins on ribosomes. These may be new enzymes to accelerate reactions or membrane carriers for ion and water transport.
System Inactivation
For the cell to be ready to receive a new signal, the cascade must be turned off. This occurs in three stages:
- G-protein inactivation. The $\alpha_s$-subunit itself possesses enzymatic (GTPase) activity. It hydrolyzes GTP to GDP, loses its affinity for adenylate cyclase, returns to the $\beta\gamma$-dimer, and halts cAMP synthesis.
- Messenger degradation. The membrane enzyme phosphodiesterase cleaves the remaining cAMP into regular AMP. Without cAMP, the regulatory subunits of PKA rebind to the catalytic ones, forming the inactive $R_2C_2$ tetramer.
- Protein dephosphorylation. The enzyme phosphoprotein phosphatase removes phosphate groups from target proteins, restoring their original structure and activity.
Note: If an inhibitory hormone acts on the receptor, a similar process is triggered via the $R_i$ receptor and $G_i$-protein. Its $\alpha_i$-subunit binds to adenylate cyclase and decreases its activity, suppressing cAMP production.
Briefly: answers to topical questions
Which hormones exert their effects via the adenylate cyclase system?
Substances that stimulate or inhibit the adenylate cyclase system act through it.
Stimulate the adenylate cyclase system (via Gs proteins):
- Glucagon
- Epinephrine (via $\beta$-receptors)
- Vasopressin (via $V_2$-receptors)
- Luteinizing hormone (LH)
- Follicle-stimulating hormone (FSH)
- Thyroid-stimulating hormone (TSH)
- Chorionic gonadotropin
- Adrenocorticotropic hormone (ACTH)
- Parathyroid hormone
- Prostaglandins of type E, D, and I
- Adrenergic catecholamines (via $\alpha_2$-, $\beta_1$-, and $\beta_2$-receptors)
Inhibit the adenylate cyclase system:
- Somatostatin
- Angiotensin II
- Acetylcholine (muscarinic effect)
- Dopamine
- Opioids
- $\alpha_2$-adrenergic catecholamines
Which bacterial toxins disrupt the function of G-proteins in the adenylate cyclase pathway?
The function of G-proteins in the adenylate cyclase pathway is disrupted by toxins with ADP-ribosyltransferase activity.
- Cholera enterotoxin (choleragen) — its A1 subunit locks the Gs protein, an adenylate cyclase regulator, in an active state. This leads to persistent activation of adenylate cyclase and accumulation of cAMP.
- E. coli LT enterotoxin (heat-labile) — structurally and mechanistically similar to cholera toxin; activates adenylate cyclase.
- Pertussis toxin (pertussis toxin / pertussin) — the A subunit ribosylates the regulatory $G_i$ protein. The toxin-modified $G_i$ protein loses its ability to regulate adenylate cyclase, resulting in uncontrolled cAMP synthesis.
Which substances are pharmacological inhibitors of phosphodiesterase?
Pharmacological inhibitors of the phosphodiesterase (PDE) enzyme are methylxanthine derivatives.
- Caffeine is a competitive PDE inhibitor.
- Theophylline causes bronchial smooth muscle relaxation (relieves bronchospasm).
- Pentoxifylline (Trental, Agapurin) is structurally related to theophylline, improves blood rheology, and has a vasodilating effect.
These substances suppress phosphodiesterase activity, leading to an increase in intracellular cAMP levels by slowing down its degradation into AMP.
Class and exam questions
How does the action of the $G_s$ protein differ from that of the $G_i$ protein?
The stimulating $G_s$ protein contains an $\alpha_s$ subunit, which upon GTP binding activates adenylate cyclase and increases cAMP synthesis. The inhibitory $G_i$ protein contains an $\alpha_i$ subunit, which, conversely, decreases the activity of this enzyme.
How does protein kinase A work?
At rest, PKA is an inactive complex of two regulatory and two catalytic subunits. When cAMP binds to the regulatory parts, the complex dissociates. The released catalytic subunits begin phosphorylating proteins at serine and threonine residues.
What role does phosphodiesterase play in the system?
Phosphodiesterase is an enzyme responsible for the degradation of the second messenger. It hydrolyzes cAMP into AMP, thereby stopping signal transduction and leading to the inactivation of protein kinase A.
What else to study on this topic
- Structure and functions of G protein-coupled receptors (GPCRs)
- GTPase activity of alpha subunits
- Specificity of protein kinase A protein targets
- Mechanisms of CREB factor interaction with DNA
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