22.2 Hormone Biochemistry & Second-Messenger Systems

Hormone Biochemistry & Second-Messenger Systems

Hormones are chemical signals produced by endocrine glands and secreted into blood to act on distant target cells. The PA-CAT Bulletin of Information, rev. 20240815 groups hormone biochemistry under Biochemistry. Mastery requires classifying hormones by chemistry, matching each class to its receptor family, and tracing the signal to its second messenger and downstream effect.

Hormone Classification by Chemistry

Peptide and protein hormones — insulin, glucagon, ACTH, FSH, LH, TSH, PTH, calcitonin, growth hormone, prolactin, oxytocin, vasopressin, and most hypothalamic releasing/inhibiting factors — are water-soluble and cannot cross the plasma membrane. They bind cell-surface receptors and act through second messengers, with rapid onset (seconds to minutes) and short half-lives. They are stored in secretory vesicles and released by exocytosis.

Steroid hormones — cortisol, aldosterone, estrogens, progesterone, testosterone, and vitamin D3 (a secosteroid) — are derived from cholesterol, lipophilic, and cross the membrane freely. They bind intracellular receptors (cytosolic or nuclear) that act as ligand-regulated transcription factors, altering gene expression over hours. Steroids are not stored in large vesicle pools; synthesis rate equals secretion rate.

Amine hormones split by chemistry. Catecholamines (epinephrine, norepinephrine, dopamine) from tyrosine act like peptide hormones at cell-surface adrenergic/dopaminergic GPCRs with fast effects. Thyroid hormones (T3, T4) from tyrosine + iodine act like steroids at nuclear receptors with slow genomic effects. This dual behavior is a classic exam contrast.

G Protein-Coupled Receptors and cAMP

Most peptide hormones bind G protein-coupled receptors (GPCRs) — seven-transmembrane receptors linked to heterotrimeric G proteins (α, β, γ). On ligand binding, GDP exchanges for GTP on the α subunit, which dissociates and modulates an effector. G proteins are named by their α subunit effect.

Gs stimulates adenylyl cyclase, converting ATP to 3′,5′-cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), which phosphorylates target proteins. Hormones using Gs include glucagon (liver), β1, β2 adrenergic agonists (heart, bronchioles), parathyroid hormone (PTH), TSH, ACTH, LH, FSH, vasopressin V2 (renal collecting duct water permeability), and calcitonin.

Gi inhibits adenylyl cyclase, lowering cAMP. Hormones using Gi include α2 adrenergic agonists (platelet aggregation, insulin inhibition in pancreatic β-cells), somatostatin, and adenosine (A1). Pertussis toxin ribosylates Giα, locking it inactive — so cells lose their brake on cAMP.

Cholera toxin ribosylates Gsα, locking it in the active GTP-bound state, persistently stimulating adenylyl cyclase. In intestinal epithelium this drives massive cAMP, opens the CFTR chloride channel, and causes secretory diarrhea.

Gq, Phospholipase C, IP3, DAG, and Calcium

Gq activates phospholipase C-β (PLC-β), which cleaves PIP2 into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 opens ER Ca2+ channels, releasing Ca2+ into cytosol. DAG plus Ca2+ activates protein kinase C (PKC). Ca2+ also binds calmodulin; the Ca2+-calmodulin complex activates CaM kinases, myosin light-chain kinase (smooth muscle contraction), and phosphorylase kinase (glycogenolysis). Hormones using Gq include α1 adrenergic (vasoconstriction), vasopressin V1 (vascular smooth muscle), angiotensin II AT1, GnRH, TRH, oxytocin, and cholecystokinin.

Receptor Tyrosine Kinases and the JAK-STAT Pathway

Receptor tyrosine kinases (RTKs) have a single transmembrane span and an intracellular kinase domain. Ligand binding drives dimerization and autophosphorylation on tyrosines, creating docking sites for downstream adaptors. Insulin receptor (a preformed heterotetramer) phosphorylates IRS-1, which activates PI3K-Akt (glucose uptake, glycogen/lipid/protein synthesis) and the Grb2-SOS-Ras-MAPK pathway (growth). Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and insulin-like growth factor-1 (IGF-1) are RTK ligands. Tamoxifen and trastuzumab target the estrogen receptor and HER2 RTK, respectively.

Cytokine receptors (growth hormone, prolactin, erythropoietin, interferons, IL-6) lack intrinsic kinase activity but recruit Janus kinases (JAKs), which phosphorylate STAT transcription factors. STATs dimerize and enter the nucleus. Growth hormone activates JAK2-STAT5 driving IGF-1 expression.

Intracellular Receptors: Steroid and Thyroid Hormones

Steroid receptors (glucocorticoid, mineralocorticoid, androgen, estrogen, progesterone, vitamin D) reside in cytosol bound to heat-shock proteins. Ligand binding releases HSP, the receptor dimerizes, and it translocates to the nucleus where it binds hormone response elements (HREs) to regulate transcription. Thyroid hormone receptor is a nuclear receptor bound to DNA even without T3 (repressing); T3 binding converts it to an activator and releases corepressors (e.g., NCoR). Effects develop over hours to days.

Endocrine Integration and Feedback

The hypothalamic-pituitary axis illustrates negative feedback: hypothalamic releasing hormones (TRH, CRH, GHRH, GnRH) drive anterior pituitary tropic hormones (TSH, ACTH, GH, LH/FSH), which drive end-organ hormones (T3/T4, cortisol, IGF-1, sex steroids), which feed back to suppress both hypothalamus and pituitary. Cortisol from CRH/ACTH suppresses further CRH and ACTH — the basis of exogenous glucocorticoid-induced adrenal suppression. This integration is a recurring PA-CAT theme and connects biochemistry to physiology and pathology.