Medservatory
USMLE Step 1MicrobiologyEP 04 of 14

Bacterial toxins that raise cAMP: cholera, pertussis, anthrax

Four toxins from four bacteria all push cyclic AMP up, but each takes a different route. Knowing the route, and the cell it acts on, predicts the clinical picture.

  • 5:54 video
  • 3 min read
  • 13 sources
  • Published 15 Nov 2026
Video lesson · 5:54 · Watch on YouTubeSeries: Microbiology · @medservatory
Chapters (12)
By the end of this lesson

Explain how cholera, pertussis, heat-labile E. coli and anthrax toxins raise cAMP, and the clinical consequences.

The short version

  1. Cholera toxin and E. coli heat-labile toxin ADP-ribosylate Gs alpha, so Gs is stuck on, cAMP rises, and chloride and water pour into the gut.
  2. Pertussis toxin ADP-ribosylates Gi alpha, so Gi is switched off and cAMP rises; the same uncoupled Gi signalling impairs lymphocyte trafficking, and lymphocytosis follows.
  3. Anthrax edema factor is itself a calmodulin-dependent adenylate cyclase; it bypasses G proteins and makes cAMP directly.
  4. Anthrax lethal factor is a zinc metalloprotease that cleaves the MAP kinase kinases (the MEKs) and kills host cells such as macrophages.
  5. The heat-stable E. coli toxin raises cyclic GMP, not cAMP, yet the result is still watery diarrhoea.

The puzzle: what tells the gut cell to secrete?

A traveller develops profuse watery diarrhoea, with stool that looks like rice water. A toxin has hijacked the gut cell's own signalling and told it to pour out chloride and water. What is the signal?

The answer is cyclic AMP. This lesson covers bacterial toxins that raise cAMP: cholera toxin, the heat-labile toxin of enterotoxigenic E. coli, pertussis toxin and anthrax toxin, and what follows clinically.[1][3]

G protein recap: how cAMP opens the chloride channel

A receptor activates Gs, which switches on adenylyl cyclase, and cyclic AMP rises. Gi does the opposite: it inhibits adenylyl cyclase.[1][2]

Each alpha subunit is on while it holds GTP, and switches itself off by hydrolysing it. Every toxin below works by breaking this switch, or by skipping it.[1]

In an intestinal cell, cyclic AMP opens the CFTR chloride channel, and sodium and water follow the chloride into the lumen.[1][3][7]

Cholera toxin and E. coli heat-labile toxin: Gs stuck on

Cholera toxin is an A-B5 toxin. Five B subunits bind GM1 ganglioside on the cell, and the A1 chain travels into the cytosol.[3][7]

A1 ADP-ribosylates Gs alpha and removes its ability to switch itself off. Gs is stuck on, adenylyl cyclase keeps working, and cyclic AMP climbs.[1][3]

The result is chloride secretion, water loss and rice-water diarrhoea.[3][7]

The heat-labile toxin of enterotoxigenic E. coli acts on Gs in the same way, and causes watery traveller's diarrhoea.[4]

Treatment follows the physiology: glucose-coupled sodium uptake through SGLT1 still works, so oral rehydration solution still works.[1][8]

Worked example: a heat-stable-only isolate
  1. A traveller has watery diarrhoea
  2. The E. coli isolate carries only a heat-stable toxin gene
  3. Heat-stable toxin activates guanylate cyclase C
  4. The raised messenger is cyclic GMP, not cyclic AMP

Pertussis toxin: Gi switched off

Pertussis toxin goes the other way. It ADP-ribosylates Gi alpha and locks it in the inactive state, so Gi can no longer inhibit adenylyl cyclase, and cyclic AMP rises.[1][2]

Pertussis toxin also causes lymphocytosis, a hallmark of whooping cough in children. The disease is paroxysmal coughing, an inspiratory whoop, and vomiting afterwards.[2][9]

Anthrax toxin: the toxin is the cyclase

Anthrax toxin works differently again. Protective antigen binds host receptors and carries two enzymes into the cell.[6][10]

Edema factor is itself an adenylate cyclase, activated by host calmodulin. It bypasses the G proteins and makes cyclic AMP directly, and fluid builds up in tissue as oedema.[6]

The other enzyme, lethal factor, is a zinc metalloprotease that cleaves the MAP kinase kinases (the MEKs) and kills host cells such as macrophages.[6]

Comparing the routes to high cAMP

Four toxins, one messenger, three routes
ToxinTargetEffect on cAMPClinical result
Cholera toxinADP-ribosylates Gs alpha (Gs stuck on)RisesRice-water diarrhoea
E. coli heat-labile toxinADP-ribosylates Gs alpha (same as cholera)RisesWatery traveller's diarrhoea
Pertussis toxinADP-ribosylates Gi alpha (Gi switched off)RisesLymphocytosis; whooping cough
Anthrax edema factorIs itself the adenylate cyclaseMade directlyOedema

In three lines: cholera is Gs on, pertussis is Gi off, and in anthrax the toxin is the cyclase.[1][3][6]

Practice question

Original · USMLE style
Your turnQB-MS-S1-MICRO-003-01

An unvaccinated 6-year-old boy has had 2 weeks of paroxysmal coughing that ends in a high-pitched inspiratory whoop, with vomiting afterwards. His white blood cell count is 31,000/mm3, with 74% lymphocytes.

Which toxin mechanism is responsible for the lymphocytosis in this patient?
Pick one option. Your answers stay on this device.

Common questions

How does cholera toxin raise cAMP?

Its A1 chain ADP-ribosylates Gs alpha and removes its ability to switch itself off. Gs stays on, adenylyl cyclase keeps working, and cyclic AMP climbs, driving chloride and water into the gut.

How does pertussis toxin raise cAMP?

It ADP-ribosylates Gi alpha and locks it in the inactive state. Gi can then no longer inhibit adenylyl cyclase, so cyclic AMP rises.

Why does anthrax edema factor not need a G protein?

Edema factor is itself an adenylate cyclase, activated by host calmodulin. It makes cyclic AMP directly, so it bypasses the G proteins.

Does the heat-stable E. coli toxin raise cAMP?

No. It activates guanylate cyclase C and raises cyclic GMP instead. The result is still watery diarrhoea.

Why does oral rehydration solution work in cholera?

Glucose-coupled sodium uptake through SGLT1 still works, so sodium and water can still be absorbed.

Transcript

Read the full narration, by chapter663 words

0:00The traveller with rice-water stool, goals and colour key

A traveller develops profuse watery diarrhoea, with stool that looks like rice water. A toxin has hijacked the gut cell's own signalling and told it to pour out chloride and water. What is the signal? Today: explain how cholera, pertussis, heat-labile E. coli and anthrax toxins raise cyclic AMP, and what follows clinically.

0:23G protein recap and how cAMP opens CFTR

Recall G proteins. A receptor activates Gs, which switches on adenylyl cyclase, and cyclic AMP rises. Gi does the opposite: it inhibits adenylyl cyclase. Each alpha subunit is on while it holds GTP, and switches itself off by hydrolysing it. In an intestinal cell, cyclic AMP opens the CFTR chloride channel, and sodium and water follow the chloride into

0:52Cholera toxin

the lumen. Cholera toxin is an A-B five toxin. Five B subunits bind GM1 ganglioside on the cell, and the A1 chain travels into the cytosol. A1 ADP-ribosylates Gs alpha and removes its ability to switch itself off. Gs is stuck on, adenylyl cyclase keeps working, and cyclic AMP climbs. The result is chloride secretion, water loss and rice-water diarrhoea.

1:23E. coli heat-labile and heat-stable toxins

Heat-labile toxin of enterotoxigenic E. coli acts on Gs in the same way, and causes watery traveller's diarrhoea. That bacterium also makes a heat-stable toxin, which raises cyclic GMP instead, by activating guanylate cyclase C. Different messenger, same watery result.

1:43Why oral rehydration still works

Treatment follows the physiology: glucose-coupled sodium uptake through SGLT1 still works, so oral rehydration solution still works. Pertussis toxin goes the other way.

1:55Pertussis toxin

It ADP-ribosylates Gi alpha and locks it in the inactive state, so Gi can no longer inhibit adenylyl cyclase, and cyclic AMP rises. Pertussis toxin also causes lymphocytosis, a hallmark of whooping cough in children. The disease is paroxysmal coughing, an inspiratory whoop, and vomiting afterwards.

2:22Anthrax toxin

Anthrax toxin works differently again. Protective antigen binds host receptors and carries two enzymes into the cell. Edema factor is itself an adenylate cyclase, activated by host calmodulin. It bypasses the G proteins and makes cyclic AMP directly, and fluid builds up in tissue as edema. The other enzyme, lethal factor, is a zinc metalloprotease that cleaves the MEK kinases and kills host cells such as macrophages.

2:54Summary and a worked example

Cholera: Gs on. Pertussis: Gi off. Anthrax: the toxin is the cyclase. Try one. A traveller has watery diarrhoea, and the E. coli isolate carries only a heat-stable toxin gene. The raised messenger is cyclic GMP, not cyclic AMP.

3:16Practice question

Your turn. An unvaccinated 6-year-old boy has had two weeks of paroxysmal coughing that ends in a high-pitched inspiratory whoop, with vomiting afterwards. His white cell count is 31,000 per cubic millimetre, with 74% lymphocytes. Which toxin mechanism is responsible for the lymphocytosis in this patient? A, ADP-ribosylation of Gs alpha in gut cells, locking it in the active GTP-bound state. B, ADP-ribosylation of elongation factor two, halting host protein synthesis. C, ADP-ribosylation of Gi alpha, blocking its inhibition of adenylyl cyclase. D, activation of the guanylate cyclase C receptor, raising intracellular cyclic GMP. E, protective antigen-delivered, calmodulin-dependent cAMP synthesis by the toxin itself. Pause here and decide.

4:21Option by option

A is out: that is the cholera and E. coli heat-labile mechanism, which acts on gut cells and causes diarrhoea. B is out: blocking elongation factor two is diphtheria toxin, which stops protein synthesis. D is out: guanylate cyclase C is the target of the heat-stable E. coli toxin, and it raises cyclic GMP. E is out: that is anthrax edema factor, delivered by protective antigen and making cyclic AMP directly, not through a G protein.

4:56The answer

So the answer is C. This is pertussis: its toxin ADP-ribosylates Gi alpha, so Gi cannot inhibit adenylyl cyclase and cyclic AMP rises. Lymphocytosis is a hallmark.

5:13Pocket card recap

Three things to keep. One: cholera and E. coli heat-labile toxin ADP-ribosylate Gs, so it is stuck on, cyclic AMP rises, and chloride and water pour into the gut. Two: pertussis toxin ADP-ribosylates Gi, so Gi is switched off, cyclic AMP rises, and lymphocytosis follows. Three: anthrax edema factor is itself a calmodulin-dependent adenylate cyclase, and lethal factor cleaves MEK. Next, the clostridial toxins compared.

Sources

Numbers in the text, e.g. [1], point here
  1. Gs/Gi and cAMP signalling: europepmc.org/article/PMC/PMC3153279
  2. Pertussis toxin: europepmc.org/article/PMC/PMC3202852 · en.wikipedia.org/wiki/Pertussis_toxin
  3. Cholera toxin: europepmc.org/article/PMC/PMC3153193
  4. E. coli heat-labile toxin: europepmc.org/article/PMC/PMC3153263 · europepmc.org/article/PMC/PMC8973357
  5. Heat-stable toxin STa and guanylate cyclase C: europepmc.org/article/PMC/PMC6356903
  6. Anthrax toxin: europepmc.org/article/PMC/PMC4810214 · en.wikipedia.org/wiki/Anthrax_toxin
  7. Virulence factors (OpenStax Microbiology 15.3): openstax.org/books/microbiology/pages/15-3-virulence-factors-of-bacterial-and-viral-pathogens
  8. Oral rehydration therapy: en.wikipedia.org/wiki/Oral_rehydration_therapy
  9. Whooping cough: en.wikipedia.org/wiki/Whooping_cough
  10. Bacterial pathogenesis (OpenStax Microbiology 15.2): openstax.org/books/microbiology/pages/15-2-how-pathogens-cause-disease
  11. Exotoxins: en.wikipedia.org/wiki/Exotoxin
  12. Adenylate cyclase toxin (not spoken): en.wikipedia.org/wiki/Adenylate_cyclase_toxin · europepmc.org/article/PMC/PMC13029963
  13. Also: europepmc.org/article/PMC/PMC11054074 · europepmc.org/article/PMC/PMC13211349 · europepmc.org/article/PMC/PMC8973357

The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.

Image credits. Servier Medical Art (CC BY 4.0, adapted): lungs, lymphocyte, boy. Servier Medical Art via bioicons (CC BY 3.0, adapted): gut cross-section, receptor strip, channel strip, water bottle. NIH BioArt (public domain): enterocyte, bacterial rod. Health Icons (CC0): cholera, diarrhoea, coughing icons. Everything else is drawn in code. No AI art.

Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-MICRO-003.

For exam study only, not medical advice. Read the medical disclaimer.

In this series

Playlist on YouTube
← Previous · EP 03Endotoxin vs exotoxin: lipid A, A-B toxins and toxoids
  1. EP 01Gram-positive vs gram-negative cell walls5:39
  2. EP 02Acid-fast stain and the mycobacterial cell wall5:01
  3. EP 03Endotoxin vs exotoxin: lipid A, A-B toxins and toxoids5:46
  4. EP 04Bacterial toxins that raise cAMP: cholera, pertussis, anthrax5:54
  5. EP 05Clostridial toxins compared: tetanus, botulinum, alpha, C. difficile5:22
  6. EP 06Staph vs strep: catalase, coagulase and haemolysis5:23
  7. EP 07Encapsulated organisms and the spleen: asplenia and conjugate vaccines5:08
  8. EP 08Bacterial genetics: how bacteria swap genes5:13
  9. EP 09Beta-lactamase and antibiotic resistance: three ways bacteria win5:13
  10. EP 10DNA vs RNA virus replication: which enzyme each genome needs5:48
  11. EP 11HIV life cycle and drug targets, step by step5:39
  12. EP 12Hepatitis B serology: reading the panel5:17
  13. EP 13Antifungal drugs explained: mechanisms of action5:26
  14. EP 14Bacterial meningitis organisms by age and risk group5:19