Components of the Adenylyl Cyclase System
The system comprises integral and membrane-anchored proteins, as well as cytosolic enzymes.
- Receptors ($R_s$ and $R_i$) — Transmembrane proteins spanning the membrane seven times (serpentine receptors). On the extracellular side, they bind the primary messenger (hormone), while on the intracellular side, they interact with G proteins. They can move freely within the lipid bilayer (lateral diffusion).
- G proteins — GTP-binding heterotrimers consisting of three subunits: $\alpha$, $\beta$, and $\gamma$. In the inactive state, the $\alpha$ subunit binds a molecule of GDP. They are broadly divided into stimulatory ($G_s$) and inhibitory ($G_i$) proteins.
- Adenylyl cyclase (AC) — A membrane-bound effector enzyme that catalyzes the synthesis of the secondary messenger.
- Protein Kinase A (PKA) — A cytosolic enzyme that directly executes the cellular response.
Activation Mechanism (The $G_s$ Pathway)
The transmission of a stimulatory signal follows a strict sequence of conformational changes:
- A hormone binds to the $R_s$ receptor, altering its spatial structure.
- The activated receptor acquires a high affinity for the inactive $G_s$ protein, forming a membrane-bound ternary complex (hormone — receptor — $G_s$-GDP).
- This interaction prompts the $\alpha_s$ subunit to release GDP and bind GTP.
- GTP binding alters the conformation of the $\alpha_s$ subunit: it dissociates from the $\beta\gamma$ dimer and diffuses freely along the membrane.
- Upon reaching adenylyl cyclase, the $\alpha_s$-GTP complex binds to its regulatory domain and activates the enzyme.
- Adenylyl cyclase converts ATP into the secondary messenger cAMP by cleaving inorganic pyrophosphate. Intracellular cAMP concentration rises sharply.
Protein Kinase A Activation and Cellular Response
The accumulation of cytosolic cAMP triggers the next step of the cascade. In its inactive state, protein kinase A exists as a tetramer $R_2C_2$, where two regulatory subunits (R) block two catalytic subunits (C).
Camp molecules bind to the regulatory subunits, causing a conformational change that lowers their affinity for the catalytic subunits. 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 addition of a phosphate group acts as a "molecular switch" that increases or decreases the activity of specific enzymes, thereby altering metabolic reaction rates.
Regulation of Gene Expression
Hormones utilizing the adenylyl 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 translocate into the nucleus, where they phosphorylate a specific transcription factor—CREB (cAMP response element-binding protein). Activated CREB-P exhibits high affinity for a regulatory DNA sequence known as the cAMP response element (CRE).
Binding to DNA stimulates the transcription of target structural genes. This yields mRNA, which is translated on ribosomes into specific proteins, such as new metabolic enzymes or membrane transporters for ions and water.
System Inactivation
For the cell to reset and respond to new signals, the cascade must be turned off. This occurs in three steps:
- G-protein inactivation. The $\alpha_s$ subunit possesses intrinsic GTPase activity. It hydrolyzes bound GTP to GDP, loses its affinity for adenylyl cyclase, reassociates with the $\beta\gamma$ dimer, and halts cAMP synthesis.
- Messenger degradation. The membrane-bound enzyme phosphodiesterase (PDE) degrades intracellular cAMP into inactive AMP. In the absence of cAMP, PKA regulatory subunits rebind to catalytic subunits, reforming the inactive $R_2C_2$ tetramer.
- Protein dephosphorylation. The enzyme phosphoprotein phosphatase removes phosphate groups from target proteins, restoring their original conformation and basal activity level.
Note: If an inhibitory hormone binds to an $i$-receptor ($R_i$), a parallel pathway is triggered via a $G_i$ protein. Its $\alpha_i$ subunit interacts with adenylyl cyclase and inhibits its activity, suppressing cAMP production.