Mechanism of Hormone Action — Receptors, G Proteins and Second Messengers by Hormone

A hormone can act only on cells that carry its receptor, and the location of the receptor follows from the chemistry of the hormone. Most signal molecules are hydrophilic and cannot cross the plasma membrane, so they bind cell-surface receptors. A few are small and hydrophobic — steroid hormones, thyroid hormones, retinoids and vitamin D — and diffuse across the membrane to bind intracellular receptors.

Steroid hormones, thyroid hormones, retinoids and vitamin D all act on members of the nuclear receptor superfamily. On binding the hormone, the receptor binds specific DNA sequences next to the genes it regulates and switches their transcription on or off. Some receptors, such as that for cortisol, sit mainly in the cytosol and enter the nucleus after binding the ligand. Others, such as the thyroid and retinoid receptors, are already bound to DNA in the nucleus even without the ligand.

In both cases the inactive receptor is held by an inhibitory protein complex. Ligand binding changes the receptor's shape, the inhibitory complex dissociates and coactivator proteins are recruited to start transcription. The response comes in waves: a small number of genes are switched on directly within about 30 minutes (the primary response), and their protein products then activate other genes in a delayed secondary response. Because new protein synthesis is needed, responses to this route typically take hours.

• Cortisol, aldosterone, sex steroids — receptor largely cytoplasmic until activated; moves to the nucleus.
• Thyroid hormone (T3) — receptor already on DNA; ligand removes the repressor complex.
• Calcitriol and retinoids — also members of the same superfamily.
• Because the response needs new protein synthesis, effects are slow in onset but can persist after the hormone has gone.

Many peptide hormones bind G-protein-coupled receptors (GPCRs) — seven-transmembrane receptors that activate a trimeric G protein. A stimulatory G protein (Gs) activates adenylyl cyclase, which converts ATP to cAMP. An inhibitory G protein (Gi) inhibits adenylyl cyclase and lowers cAMP. cAMP is broken down continuously by phosphodiesterases to 5'-AMP, which is why the signal is rapid: an extracellular signal can change cAMP more than twenty-fold within seconds. cAMP acts mainly by activating protein kinase A (PKA), which phosphorylates target proteins on serine or threonine residues.

Examples worth knowing: glucagon binds a Gs-coupled receptor, stimulates adenylyl cyclase and activates PKA, the principal pathway for its liver effects. TSH, LH, FSH and hCG share the same α subunit and act through the cAMP system. The ACTH receptor (MC2R) couples to Gαs, raising cAMP in the adrenal cortex. GHRH stimulates cAMP in the somatotroph, while somatostatin receptors lower cAMP.

Receptors that couple to Gq activate phospholipase C-β. This enzyme cleaves the membrane phospholipid PIP2 (phosphatidylinositol 4,5-bisphosphate) into two messengers, and the pathway then splits into two branches.

A rise in cAMP or Ca²⁺ acts mainly by stimulating PKA and CaM-kinases respectively, while PKC, PKA and CaM-kinases all phosphorylate proteins on serine or threonine. Hormones using this route include GnRH (GnRH receptors couple primarily to Gq/11), TRH and the V1 receptor of vasopressin (vasoconstriction). The TSH receptor is unusual: it couples to both Gs and Gq. The Gs/cAMP arm drives iodide uptake, thyroid hormone secretion and growth, while the Gq/calcium arm is rate-limiting for thyroid hormone synthesis.

The remaining cell-surface receptors are enzyme-linked receptors, in which the receptor itself is an enzyme or is tightly bound to one.

cGMP is destroyed by a phosphodiesterase. Sildenafil and other PDE5 inhibitors act by slowing this breakdown in the penis, so cGMP stays elevated for longer after local nitric oxide release.

• Cholera — Gs locked on by toxin; cAMP high; secretory diarrhoea.
• Pertussis — Gi inactivated; cAMP effects unopposed.
• McCune–Albright syndrome — activating GNAS (Gsα) mutation, mosaic; polyostotic fibrous dysplasia, irregular café-au-lait-type macules, precocious puberty and other autonomous endocrine hyperfunction.
• Pulsatile vs continuous GnRH — pulsatile release maintains LH and FSH; continuous GnRH gives an initial rise then desensitisation, which is exploited therapeutically with GnRH analogues.
• PDE5 inhibitors (sildenafil) — raise cGMP by blocking its breakdown.
• Time course — responses that only change existing proteins take seconds or milliseconds; responses needing gene expression take hours.

The same hormone can produce different responses in different cells because each cell type has its own set of target proteins for PKA, PKC and the other kinases. In fat cells, for example, at least four hormones activate adenylyl cyclase and all of them stimulate triglyceride breakdown.