Adenylate cyclase system
The adenylate cyclase system is a non-catalytic mechanism of transmembrane signal transduction and includes three main components: a receptor (R-protein), a G-protein, and the enzyme adenylate cyclase. The receptor can be stimulatory (Rs) or inhibitory (Ri). The G-protein consists of three subunits — α, β, and γ; in the inactive state, a GDP molecule is bound to the α-subunit.
Activation is triggered by hormone binding to the Rs-protein, which alters its conformation and enables contact with the α-subunit. The α-subunit loses its affinity for GDP and acquires an affinity for GTP. Upon GTP binding, the α-subunit dissociates from the βγ-complex and moves via lateral diffusion to adenylate cyclase. The resulting α-GTP–adenylate cyclase complex catalyzes the conversion of ATP into cAMP.
cAMP binds to regulatory subunits of protein kinase A, causing their dissociation and the activation of catalytic subunits. Protein kinase A phosphorylates target proteins at serine and threonine residues using ATP. Inactivation of the system is ensured by the intrinsic GTPase activity of the α-subunit: GTP is hydrolyzed to GDP, and the α-subunit returns to the βγ-complex. Upon interaction with the Ri protein, αi-GTP inhibits adenylate cyclase, the cAMP concentration decreases, protein kinase A reassociates, and protein phosphorylation diminishes.
Inositol phosphate system
This system is also non-catalytic and includes a receptor, a Gq-protein, and the enzyme phospholipase C (PLC). The principle of α-subunit activation is analogous to the previous system: GTP binding, dissociation from the βγ-complex, and activation of PLC.
Phospholipase C hydrolyzes membrane phosphatidylinositol-4,5-bisphosphate (PIP₂) to yield two second messengers: diacylglycerol (DAG), which remains in the membrane, and inositol-1,4,5-trisphosphate (IP₃), which enters the cytosol.
- IP₃ binds to calcium channels of the endoplasmic reticulum, causing them to open; Ca²⁺ ions enter the cytosol down their concentration gradient.
- Ca²⁺ binds to the protein calmodulin (4 binding sites), and the resulting complex activates Ca²⁺-calmodulin-dependent protein kinases, which phosphorylate proteins at serine and threonine residues.
- Ca²⁺ together with DAG and phosphatidylserine activates protein kinase C, which also phosphorylates proteins at serine and threonine residues.
Catalytic receptors: insulin and ANP
Catalytic receptors include the insulin receptor and the atrial natriuretic peptide (ANP) receptor. The insulin receptor is a tetramer composed of two α- and two β-subunits; the β-subunits possess tyrosine kinase activity.
Upon insulin binding to the α-subunits, the β-subunits autophosphorylate tyrosine residues and also phosphorylate IRS proteins (insulin receptor substrates). Effects of the signaling cascade:
- increased glucose transport in insulin-dependent tissues through the insertion of GLUT-4 into the membrane;
- activation of phosphoprotein phosphatase, which dephosphorylates enzymes of glycogen synthesis and glycolysis;
- activation of phosphodiesterase, which degrades cAMP and suppresses the adenylate cyclase system;
- alteration of the expression of specific protein genes.
The guanylate cyclase system operates for ANP. The receptor itself is a guanylate cyclase; upon ligand binding, it catalyzes the conversion of GTP to cGMP. cGMP activates protein kinase G (an analogue of protein kinase A), which phosphorylates target proteins.
Intracellular receptors
Hydrophobic hormones (e.g., cortisol and other steroids) freely cross the cytoplasmic membrane and bind to intracellular receptors. The hormone-receptor complex moves into the nucleus and interacts with specific DNA regions:
- binding to an enhancer increases the transcription of the corresponding genes;
- binding to a silencer suppresses transcription.
Changes in the rate of protein synthesis lead to metabolic reorganization of the cell. This pathway is characteristic of steroid and thyroid hormones.
Choice of signal transduction pathway and hormone examples
The type of system used is determined by the physicochemical properties of the hormone. Hydrophilic hormones do not cross the lipid bilayer and act via membrane receptors (adenylate cyclase, inositol phosphate, and catalytic systems). Hydrophobic hormones pass through the membrane and act via intracellular receptors.
- Adenylate cyclase system: adrenaline (via β-receptors), glucagon.
- Inositol phosphate system: angiotensin II, adrenaline in the liver (α₁-receptors), ADH (vasopressin) via smooth muscle V₁-receptors.
- Catalytic receptors: insulin (tyrosine kinase), ANP (guanylyl cyclase).
- Intracellular receptors: cortisol and other steroid hormones.
Key points
- The adenylate cyclase and inositol phosphate systems are non-catalytic, while the insulin and ANP receptors are catalytic.
- The G-protein α-subunit exhibits GTPase activity, which ensures self-inactivation of the system.
- Secondary messengers include cAMP, cGMP, IP₃, DAG, and Ca²⁺ ions.
- Phospholipase C hydrolyzes PIP₂ into IP₃ and DAG; IP₃ mobilizes Ca²⁺ from the ER.
- The insulin receptor possesses tyrosine kinase activity and activates the insertion of GLUT-4 into the membrane.
- Protein kinases A, G, C, and Ca²⁺-calmodulin-dependent protein kinase phosphorylate proteins at serine and threonine residues.
- Hydrophilic hormones act via membrane receptors, whereas hydrophobic (steroid) hormones act via intracellular receptors.
- Steroid hormones regulate transcription by binding to DNA enhancers or silencers.