21. In small intestine, cholera toxin acts by
(1) active absorption of NaCl
(2) activation of GTPase
(3) inhibition of adenylyl cyclase
(4) ADP-ribosylation of the G-protein

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Introduction

Cholera toxin, produced by Vibrio cholerae, causes severe watery diarrhea through its action on intestinal epithelial cells. To grasp its molecular mechanism is crucial for understanding cholera disease pathology and developing treatment strategies.

Mechanism of Action in Small Intestine

• Cholera toxin binds to the GM1 ganglioside receptor on the surface of intestinal epithelial cells (enterocytes).

• The toxin is endocytosed and transported retrogradely to the endoplasmic reticulum, where the enzymatic A1 subunit becomes active.

• The A1 subunit catalyzes ADP-ribosylation of the G protein alpha subunit (Gsα), locking it in its GTP-bound, active state.

• This persistent activation continuously stimulates adenylate cyclase, increasing intracellular cyclic AMP (cAMP) levels.

• Elevated cAMP opens cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels, causing efflux of chloride ions and water into the intestinal lumen, resulting in diarrhea.

Why Option 4 Is Correct

Among the options:

1. Active absorption of NaCl — Incorrect; cholera toxin increases secretion, not absorption.

2. Activation of GTPase — Incorrect; cholera toxin inhibits GTPase activity of the G protein.

3. Inhibition of adenylyl cyclase — Incorrect; toxin activates adenylate cyclase.

4. ADP-ribosylation of the G-protein — Correct; key biochemical step by which cholera toxin exerts its effect.

Summary

Cholera toxin acts by ADP-ribosylation of the G-protein, leading to continuous adenylate cyclase activity and disrupted ion transport in enterocytes, causing diarrhea.

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