Hormone Signaling Pathways & Binding Proteins

Hormone chemistry predicts behavior

Peptides. Insulin, ACTH, PTH and glucagon are translated as preprohormones, trimmed in the Golgi and stored in secretory granules until Ca²⁺-triggered exocytosis. Being water-soluble, they circulate mostly unbound, last minutes and act on cell-surface receptors. Most are digested if swallowed, so insulin must be injected.

Steroids. Cortisol, aldosterone, sex steroids and calcitriol are made from cholesterol on demand rather than stored. They are lipophilic, travel on binding proteins, last hours, are absorbed intact by mouth and act on intracellular receptors that change transcription.

Amines split. Tyrosine-derived catecholamines behave like peptides (granules, surface GPCRs, half-life about 2 minutes), whereas thyroid hormones behave like steroids: over 99% protein-bound, nuclear receptors, half-life about 7 days for T4 and 1 day for T3; like steroids, levothyroxine works by mouth.

G protein–coupled receptors

Gs. Gsα-GTP stimulates adenylyl cyclase; cAMP activates protein kinase A, which phosphorylates enzymes, channels and CREB, until phosphodiesterase degrades cAMP. At V2, ADH inserts aquaporin-2 into the collecting duct. Gsα (GNAS) gain-of-function in McCune-Albright syndrome causes autonomous hyperfunction such as precocious puberty; loss-of-function in pseudohypoparathyroidism type 1a causes PTH resistance.

Gq. Phospholipase C splits PIP₂ into IP₃, which releases Ca²⁺ from the ER, and DAG, which activates protein kinase C.

cGMP. ANP and BNP bind receptors with built-in (membrane) guanylyl cyclase, producing vasodilation, natriuresis and lower renin and aldosterone. NO diffuses into smooth muscle and activates soluble guanylyl cyclase; cGMP then activates protein kinase G and relaxes the muscle. Nitrates donate NO, and PDE5 inhibitors such as sildenafil block cGMP breakdown.

CRH and GHRH use cAMP, but GnRH and TRH use Gq. ADH constricts vessels through V1 (Gq) yet concentrates urine through V2 (Gs): the receptor subtype picks the messenger.

Kinase-linked receptors

Intrinsic tyrosine kinases. Insulin, IGF-1, FGF, PDGF and EGF bind receptors whose cytoplasmic domains are tyrosine kinases. Binding causes dimerization (the insulin receptor is a preformed α₂β₂ tetramer) and autophosphorylation, recruiting docking proteins such as IRS-1 that feed PI3K/Akt (metabolic effects, GLUT4 translocation) and Ras/MAPK (growth). EGFR and HER2 overactivity drives lung and breast cancers, targeted by erlotinib and trastuzumab.

JAK/STAT. GH, prolactin, erythropoietin, thrombopoietin, G-CSF and cytokines such as IL-2, IL-6 and interferons bind receptors without intrinsic kinase activity. The occupied receptor activates associated Janus kinases, which phosphorylate STATs that dimerize and enter the nucleus. JAK2 V617F makes erythropoietin and thrombopoietin signaling ligand-independent in polycythemia vera, essential thrombocythemia and myelofibrosis (CML instead carries the BCR-ABL fusion kinase).

Intracellular receptors

Mechanism. Cortisol, aldosterone, sex steroids, T3 and calcitriol cross the membrane. Glucocorticoid, mineralocorticoid and androgen receptors wait in the cytoplasm bound to heat-shock proteins; estrogen, thyroid and vitamin D receptors are mainly nuclear. The hormone-receptor complex binds hormone response elements on DNA, so effects take hours to days. In androgen insensitivity, a defective androgen receptor leaves a 46,XY person phenotypically female despite normal-to-high testosterone.

Binding proteins and the free-hormone principle

Principle. Thyroxine-binding globulin (TBG), sex hormone–binding globulin (SHBG), cortisol-binding globulin (CBG, transcortin) and albumin hold most lipophilic hormone as an inactive reservoir that prolongs half-life. Only the free fraction enters cells and is sensed by feedback, so when carrier levels change, total hormone moves while free hormone and the patient stay normal.

Clinical consequences. Estrogen raises TBG through more hepatic synthesis and slower clearance, lifting total T4 while free T4 and TSH stay normal; nephrotic syndrome does the reverse through urinary loss. SHBG binds testosterone more tightly than estradiol; hyperinsulinemia suppresses hepatic SHBG, raising free testosterone and fueling hirsutism in PCOS, and obese men can have low total but normal free testosterone. Estrogen-driven CBG excess raises total cortisol and can produce a false-positive dexamethasone suppression test. Albumin binds many hormones weakly but with great capacity, so hypoalbuminemia lowers total cortisol and total calcium while free cortisol and ionized calcium are normal.