G protein-coupled receptors and cAMP !

The largest receptor family: the hormone binds outside, a G protein switches on inside and a second messenger amplifies the signal.

Updated 2026-11-01

Key facts

Seven transmembrane helices; the G protein is an αβγ trimer that swaps GDP for GTP when activated.
Gαs activates adenylyl cyclase (cAMP rises); Gαi inhibits it (cAMP falls); Gαq activates phospholipase C (IP₃ and DAG).
cAMP activates PKA; phosphodiesterase breaks it down to AMP and ends the signal.
Cholera toxin keeps Gαs always on; pertussis toxin stops Gαi from switching on.
Hormones using Gs/cAMP: glucagon, adrenaline (β), ACTH, TSH, LH, FSH, PTH, ADH in the kidney (V2), CRH, GHRH and calcitonin.

The hormone holds the receptor in its active shape, which acts as an exchanger: the α subunit lets go of GDP, takes GTP and leaves βγ.
Gαs-GTP binds adenylyl cyclase and activates it: ATP → cAMP + pyrophosphate. One hormone molecule yields thousands of cAMP molecules (amplification).
cAMP binds PKA's regulatory subunits and frees the catalytic ones, which phosphorylate enzymes, channels and the transcription factor CREB.
The α subunit hydrolyses its own GTP (GTPase activity, sped up by RGS proteins) and rejoins βγ: the signal switches itself off.
The active receptor is desensitised: GRK kinases phosphorylate it, β-arrestin binds and removes it from the membrane by endocytosis.
βγ subunits also signal: they open K⁺ channels (GIRK) in the heart after vagal stimulation.

Cholera causes massive watery diarrhoea because high cAMP in the enterocyte opens the CFTR channel and chloride leaves with water into the gut lumen.
Mosaic activating GNAS mutations cause McCune–Albright syndrome (fibrous dysplasia, café-au-lait spots, precocious puberty); in the pituitary they cause GH-secreting adenomas.
Inactivating GNAS mutations cause pseudohypoparathyroidism: high PTH with no kidney response.
About a third of drugs act on GPCRs (beta-blockers, antihistamines, opioids, GLP-1 agonists).

Think of the answer, then tap the question to see it.

What does cholera toxin do to Gαs?

It ADP-ribosylates it and blocks its GTPase activity; Gαs stays on, cAMP rises and the enterocyte secretes chloride and water.

Which Gα subunit activates phospholipase C?

Gαq; it makes IP₃ and diacylglycerol from PIP₂.

How is a G protein signal switched off?

The α subunit hydrolyses its GTP to GDP and rejoins βγ; phosphodiesterase also breaks down cAMP.

Which proteins desensitise a G protein-coupled receptor?

GRK kinases, which phosphorylate it, and β-arrestin, which blocks the G protein and internalises it.

Educational information, not medical advice. For any symptom, see a health professional.

Sources: GNAS gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); GNAS: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (human) (UniProt, 2026); McCune-Albright syndrome: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); 4CLK: Crystal structure of human soluble Adenylyl Cyclase in complex with alpha,beta-methyleneadenosine-5'-triphosphate (RCSB Protein Data Bank, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Representative model, for educational purposes only.