17.4 Hormones, Receptors, Second Messengers & Signal Transduction
Key Takeaways
Water-soluble peptide and catecholamine hormones act on cell-surface receptors through second messengers, while lipid-soluble steroid and thyroid hormones (and vitamin D) bind intracellular nuclear receptors that act as transcription factors.
Gs-coupled receptors raise cAMP and activate protein kinase A, Gi-coupled receptors lower cAMP, and Gq-coupled receptors activate phospholipase C to produce IP3 (calcium release) and DAG (protein kinase C).
Insulin and growth factors (PDGF, EGF, FGF, VEGF, IGF-1) signal through receptor tyrosine kinases, cytokines through JAK-STAT, TGF-beta through serine/threonine kinase receptors and SMADs, and nitric oxide and natriuretic peptides through cGMP.
Cholera toxin ADP-ribosylates Gs alpha (locking it active), pertussis toxin ADP-ribosylates Gi alpha (blocking inhibition), and both raise cAMP.
Only free (unbound) hormone is active; plasma transport proteins such as thyroxine-binding globulin, cortisol-binding globulin and sex hormone-binding globulin change total but not free hormone levels.
17.4 Hormones, Receptors, Second Messengers & Signal Transduction
The biochemistry outline lists hormones, second messengers and signal transduction, with subtopics of growth factors, receptors, steroids and thyroid hormones, plasma transport proteins and glucose-regulating hormones. Endocrine gland physiology is in 16.3. This section explains the molecular signaling those hormones and many drugs use, including beta-agonists, insulin, phosphodiesterase inhibitors, JAK inhibitors and corticosteroids.
Hormone Classes
| Class | Examples | Solubility and transport | Receptor location | Speed |
|---|---|---|---|---|
| Peptide and protein | Insulin, glucagon, PTH, ACTH, growth hormone | Water-soluble; mostly free in plasma | Cell surface | Seconds to minutes |
| Amine (catecholamine) | Epinephrine, norepinephrine, dopamine | Water-soluble | Cell surface | Seconds |
| Amine (thyroid) | T4, T3 | Lipid-soluble; bound to TBG, transthyretin, albumin | Nuclear (thyroid hormone receptor with RXR) | Hours to days |
| Steroid | Cortisol, aldosterone, estrogen, testosterone, calcitriol | Lipid-soluble; bound to carrier proteins | Cytoplasmic or nuclear | Hours |
| Eicosanoids | Prostaglandins, thromboxanes, leukotrienes | Local (paracrine) | Cell surface G-protein-coupled receptors | Seconds |
Plasma transport proteins. Only the free fraction binds receptors and is cleared. Cortisol-binding globulin (transcortin), sex hormone-binding globulin, thyroxine-binding globulin (TBG) and albumin act as reservoirs. Estrogen (pregnancy, oral contraceptives) raises TBG, which increases total T4 while free T4 stays normal, so free hormone levels are the ones to interpret.
G-Protein-Coupled Receptors
GPCRs have seven transmembrane helices and couple to heterotrimeric G proteins (alpha, beta and gamma subunits). Ligand binding causes the alpha subunit to exchange GDP for GTP and separate from beta-gamma. The alpha subunit's own GTPase activity ends the signal.
| G protein | Effector | Second messenger | Representative receptors |
|---|---|---|---|
| Gs | Activates adenylyl cyclase | Increased cAMP, which activates protein kinase A | Beta-1, beta-2, D1, H2, V2, glucagon, PTH, TSH, ACTH, FSH, LH, calcitonin, GHRH |
| Gi | Inhibits adenylyl cyclase | Decreased cAMP; opens K+ channels | Alpha-2, M2, D2, opioid receptors |
| Gq | Activates phospholipase C | IP3 (releases Ca2+ from the ER) and DAG (activates protein kinase C) | Alpha-1, M1, M3, H1, V1, AT1, GnRH, TRH, oxytocin, gastrin |
Phosphodiesterases (PDEs) degrade cAMP and cGMP. Inhibitors amplify these signals:
- Theophylline and caffeine (nonselective)
- Cilostazol (PDE3) for claudication
- Roflumilast (PDE4) for COPD
- Sildenafil (PDE5) for erectile dysfunction
Bacterial toxins also target G proteins:
- Cholera toxin ADP-ribosylates Gs alpha, which locks it in the GTP-bound active state; cAMP rises and intestinal chloride secretion causes watery diarrhea.
- Pertussis toxin ADP-ribosylates Gi alpha, which prevents inhibition of adenylyl cyclase, so cAMP also rises.
cGMP Signaling
- Soluble guanylyl cyclase is activated by nitric oxide (endothelial NO, nitroglycerin and nitroprusside). It raises cGMP and protein kinase G activity, causing smooth muscle relaxation and vasodilation.
- Membrane (particulate) guanylyl cyclase is the receptor for ANP and BNP, which cause natriuresis and vasodilation.
Enzyme-Linked Receptors
| Receptor class | Ligands | Pathway | Clinical connection |
|---|---|---|---|
| Receptor tyrosine kinases | Insulin, IGF-1, PDGF, EGF, FGF, VEGF, NGF | Ligand-induced dimerization and autophosphorylation; insulin acts through IRS-1, then PI3K/Akt (GLUT4 translocation, glycogen synthesis) and Ras/MAPK (growth) | Insulin resistance; becaplermin (PDGF) for ulcers; EGFR and VEGF inhibitors in cancer (12.4) |
| Non-receptor tyrosine kinase (JAK-STAT) | Cytokines (IL-2, IL-6, interferons), growth hormone, prolactin, erythropoietin, G-CSF, thrombopoietin | Receptor-associated JAKs phosphorylate STATs, which dimerize and enter the nucleus | JAK inhibitors (tofacitinib) in RA; JAK2 V617F in polycythemia vera (9.1) |
| Serine/threonine kinase receptors | TGF-beta, bone morphogenetic proteins | Phosphorylate SMAD proteins | TGF-beta drives fibrosis and wound matrix; BMPs drive bone formation (bone graft substitutes) |
| Ligand-gated ion channels | Acetylcholine (nicotinic), GABA-A, glutamate | Direct ion flux | Neuromuscular blockers, benzodiazepines |
Growth factors in tissue repair. PDGF (platelets, macrophages) recruits fibroblasts and smooth muscle cells. VEGF drives angiogenesis in granulation tissue. FGF-2 supports angiogenesis and fibroblast proliferation. EGF and KGF stimulate re-epithelialization. TGF-beta stimulates collagen synthesis and myofibroblast contraction (7.2).
Nuclear (Intracellular) Receptors
Lipophilic ligands cross the membrane and bind receptors that act as ligand-activated transcription factors at hormone response elements in DNA:
- Glucocorticoid receptor: cytoplasmic and held by HSP90. After ligand binding it moves to the nucleus to induce genes such as annexin A1 (lipocortin) and to repress NF-kB-driven genes (11.3).
- Mineralocorticoid, estrogen, progesterone and androgen receptors.
- Thyroid hormone, vitamin D (VDR), retinoic acid and PPAR receptors, which partner with RXR. PPAR-gamma is the target of pioglitazone (12.2).
Steroid and Thyroid Hormone Synthesis
- Steroids are made from cholesterol. Delivery of cholesterol to the inner mitochondrial membrane by StAR and cleavage by side-chain cleavage enzyme (CYP11A1, desmolase) to pregnenolone are the rate-limiting steps, stimulated by ACTH (adrenal) or LH (gonads). 21-hydroxylase deficiency, the most common form of congenital adrenal hyperplasia, lowers cortisol and aldosterone and shunts precursors into androgens. Calcitriol, the secosteroid form of vitamin D, is covered in 16.3.
- Thyroid hormones: iodide is trapped by the Na+/I- symporter, then oxidized and attached to thyroglobulin tyrosines by thyroid peroxidase (blocked by methimazole and propylthiouracil). Coupling forms T4 and T3. Peripheral 5'-deiodinase converts T4 to the more active T3; PTU and high-dose glucocorticoids inhibit this step.
Glucose-Regulating Hormones
Insulin secretion by the beta cell:
- Glucose enters through GLUT2 and is phosphorylated by glucokinase, the glucose sensor.
- The rising ATP/ADP ratio closes K-ATP channels (the target of sulfonylureas, 12.2).
- Membrane depolarization opens voltage-gated Ca2+ channels.
- Calcium influx triggers insulin exocytosis. Incretins (GLP-1, GIP) amplify secretion through Gs and cAMP.
Insulin actions: glucose uptake through GLUT4 in muscle and fat, glycogen and fat synthesis, protein synthesis, potassium uptake into cells, and inhibition of lipolysis, ketogenesis and hepatic glucose output.
Counterregulatory hormones:
- Glucagon (Gs and cAMP in the liver): glycogenolysis, gluconeogenesis, ketogenesis
- Epinephrine (beta-2 and alpha): glycogenolysis, lipolysis, suppression of insulin through alpha-2
- Cortisol: gluconeogenesis, insulin resistance; it is permissive for glucagon and catecholamine effects
- Growth hormone: lipolysis and insulin resistance
These counterregulatory hormones explain stress hyperglycemia after trauma, surgery or infection and why corticosteroid injections or systemic courses raise glucose in people with diabetes for several days.
Signal Termination and Desensitization
Signals stop through GTP hydrolysis, phosphodiesterases and phosphatases. With repeated stimulation, GPCR kinases and beta-arrestin uncouple and internalize receptors (desensitization and downregulation). This explains tachyphylaxis to repeated beta-agonist doses and the rebound effects after withdrawing a receptor blocker (10.3).
Which second-messenger pathway mediates the vasoconstriction caused by an alpha-1 adrenergic agonist such as phenylephrine?
Gq activation of phospholipase C, generating IP3 (calcium release) and DAG (protein kinase C)
Gs activation of adenylyl cyclase, raising cAMP and protein kinase A activity in smooth muscle
Soluble guanylyl cyclase activation, raising cGMP and protein kinase G
JAK phosphorylation of STAT transcription factors
A pregnant patient has an elevated total T4 but a normal free T4 and normal TSH. What is the best explanation?
Iodine deficiency stimulating thyroid peroxidase
Primary hyperthyroidism from Graves disease
Estrogen-induced rise in thyroxine-binding globulin
Increased peripheral deiodinase activity converting T4 to T3
Which receptor mechanism does insulin use to cause GLUT4 translocation in skeletal muscle?
A Gi-coupled receptor that lowers cAMP
A nuclear receptor that binds a hormone response element in DNA
A ligand-gated chloride channel
A receptor tyrosine kinase signaling through IRS-1 and PI3K/Akt
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