22. The mode of action of cholera toxin in causing diarrhoea is by:
(1) inactivating G_i protein.
(2) continuousactivation of adenylyl cyclase.
(3) locking G_S protein in an inactive state.
(4)rapidly hydrolyzing GTP to GDP

Cholera Toxin Mechanism in Small Intestine: Continuous Adenylyl Cyclase Activation

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Introduction

Cholera toxin, produced by Vibrio cholerae, is the principal cause of severe watery diarrhea seen in cholera infection. The toxin disrupts normal cellular signaling in the small intestine’s epithelial cells, leading to an excessive secretion of water and electrolytes into the intestinal lumen.

Molecular Mechanism of Cholera Toxin

• Cholera toxin binds to the GM1 ganglioside receptors on the intestinal epithelial cell surface and is endocytosed.

• The enzymatic A1 subunit of the toxin catalyzes ADP-ribosylation of the Gs alpha subunit (Gs) of the heterotrimeric G protein.

• This modification locks Gs in an active GTP-bound state by inactivating its intrinsic GTPase activity.

• Constitutively active Gs persistently stimulates adenylyl cyclase, causing a dramatic increase in intracellular cyclic AMP (cAMP) levels.

• Elevated cAMP activates the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, increasing chloride ion secretion into the intestinal lumen.

• Sodium and water follow the ionic gradient osmotically, resulting in profuse watery diarrhea characteristic of cholera.

Analysis of Options

(1) Inactivating Gi protein: Incorrect. Cholera toxin acts on Gs, not the inhibitory G protein (Gi).

(2) Continuous activation of adenylyl cyclase: Correct. Persistent stimulation of adenylyl cyclase leads to elevated cAMP and the diarrheal response.

(3) Locking Gs protein in an inactive state: Incorrect. It locks Gs protein in its active state.

(4) Rapidly hydrolyzing GTP to GDP: Incorrect. Cholera toxin inhibits GTP hydrolysis, preventing inactivation.

Summary

The mode of action of cholera toxin causing diarrhea is by continuous activation of adenylyl cyclase (option 2) via ADP-ribosylation of the Gs protein which prevents its GTPase activity and keeps it active.

This molecular disruption results in excessive cAMP generation, ionic imbalance, and massive fluid secretion into the intestinal lumen.

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