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[Biochemistry](https://durgical.com/en/biochemistry/) · Topic

# 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.

## In detail

- 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.

**Also called**
GPCR, Seven-transmembrane receptors

## Clinical notes

- 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).

## Related conditions

- [Pituitary adenoma](https://durgical.com/en/conditions/pituitary-adenoma/)
- [Cushing syndrome](https://durgical.com/en/conditions/cushing-syndrome/)

## Related

- [Adenylyl cyclase](https://durgical.com/en/biochemistry/enzymes/adenylyl-cyclase/)
- [Protein kinase A (PKA)](https://durgical.com/en/biochemistry/enzymes/protein-kinase-a/)
- [Cyclic AMP (cAMP)](https://durgical.com/en/biochemistry/molecules/cyclic-amp/)
- [IP₃, DAG and calcium pathway](https://durgical.com/en/biochemistry/topics/ip-dag-and-calcium-pathway/)
- [Glucagon signalling](https://durgical.com/en/biochemistry/topics/glucagon-signalling/)
- [Adrenaline](https://durgical.com/en/biochemistry/molecules/adrenaline/)
- [Hormone classes and mechanisms](https://durgical.com/en/biochemistry/topics/hormone-classes-and-mechanisms/)

## Test yourself

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.

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

Sources: [GNAS gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/gnas/) (MedlinePlus, US National Library of Medicine, 2026); [GNAS: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (human)](https://www.uniprot.org/uniprotkb/P63092/entry) (UniProt, 2026); [McCune-Albright syndrome: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/mccune-albright-syndrome/) (MedlinePlus, US National Library of Medicine, 2026); [4CLK: Crystal structure of human soluble Adenylyl Cyclase in complex with alpha,beta-methyleneadenosine-5'-triphosphate](https://www.rcsb.org/structure/4CLK) (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.

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