Question

The gram-negative bacterium Vibrio cholerae produces a protein, cholera toxin $(M_{\mathrm{r}}90,000)$, that is responsible for the characteristic symptoms of cholera: extensive loss of body water and ${\mathrm{Na}}^{+}$through continuous, debilitating diarrhea. If body fluids and ${\mathrm{Na}}^{+}$are not replaced, severe dehydration results; untreated, the disease is often fatal. When the cholera toxin gains access to the human intestinal tract, it binds tightly to specific sites in the plasma membrane of the epithelial cells lining the small intestine, causing adenylyl cyclase to undergo prolonged activation (hours or days). a. What is the expected effect of cholera toxin on [cAMP] in the intestinal cells? b. Based on the information above, suggest how cAMP normally functions in intestinal epithelial cells. c. Suggest a possible treatment for cholera.

Short answer

Cholera toxin increases [cAMP], leading to ion and water loss. Rehydration therapy is crucial for treatment.

Step-by-step solution

Examine the effect of cholera toxin on adenylyl cyclase

Cholera toxin causes prolonged activation of adenylyl cyclase in intestinal epithelial cells. This enzyme is responsible for converting ATP to cAMP (cyclic adenosine monophosphate). With its prolonged activation, there will be an increased production of cAMP in the cells.

Assess effect on [cAMP] in intestinal cells

Given the prolonged activation of adenylyl cyclase, the concentration of cAMP (cyclic adenosine monophosphate) is expected to increase significantly in the intestinal epithelial cells.

Understand cAMP's function in intestinal cells

Normally, cAMP acts as a secondary messenger in cellular signaling pathways. In intestinal epithelial cells, elevated cAMP levels lead to the opening of chloride channels, resulting in chloride ion secretion into the intestinal lumen, followed by water and sodium ions due to osmotic and electrochemical gradients.

Propose a treatment for cholera

A possible treatment for cholera would involve rehydration therapy, typically with oral rehydration salts. This treatment replaces fluids and electrolytes lost through diarrhea. Furthermore, inhibitors that suppress cAMP production or action may also help alleviate symptoms of cholera.

Key concepts

cAMP Signaling

cAMP, or cyclic adenosine monophosphate, is a crucial molecule that acts as a secondary messenger in many biological signaling pathways. In simple terms, it's like a relay race where cAMP is the baton passed from one molecule to another to convey information.
In the context of intestinal epithelial cells, cAMP plays a pivotal role by mediating the effects of hormones like epinephrine and glucagon. When the hormone binds to its receptor on the cell surface, it activates adenylyl cyclase, an enzyme that catalyzes the conversion of ATP to cAMP.
This influx of cAMP triggers various responses in the cell, such as the opening of chloride channels on the cell membrane. This leads to the secretion of chloride ions into the intestinal lumen. Water and sodium ions follow due to osmotic pressure and electrochemical gradients, which is the normal process. However, when overly enhanced, such as during cholera infection, this process can lead to severe dehydration due to excessive loss of water and ions.

Adenylyl Cyclase Activation

Adenylyl cyclase is an enzyme responsible for producing cAMP from ATP. It's like a switch that turns on the production of this signaling molecule when a command is given by a receptor hormone.
In typical conditions, adenylyl cyclase is activated briefly, ensuring a controlled production of cAMP. However, cholera toxin disrupts this balance by causing the adenylyl cyclase to remain activated for an extended period. This is akin to a fire alarm continuously blaring without anyone turning it off.
The prolonged adenylyl cyclase activation caused by cholera toxin leads to sustained high levels of cAMP within the intestinal cells. This excessive cAMP messes up the normal electrolyte and fluid balance in the intestines, resulting in extensive water and sodium loss. This imbalance is what causes the severe diarrhea associated with cholera.

Oral Rehydration Therapy

Oral Rehydration Therapy (ORT) is a crucial life-saving treatment for managing dehydration caused by diseases like cholera. It's a simple, yet highly effective method.
ORT involves drinking a solution containing clean water, salts, and sugar. This solution replaces the fluids and electrolytes lost due to severe diarrhea. The presence of sugar (usually glucose) is vital because it helps enhance the absorption of sodium and water in the intestines.
Using ORT can substantially reduce mortality rates in cholera outbreaks as it tackles the primary threat of dehydration. It's affordable, easy to administer, and can be given at home, making it an accessible treatment option in resource-limited settings.
In addition to ORT, research is ongoing into developing other therapies. These include drugs or compounds to inhibit excessive cAMP production or action, aiming to reduce the severity of symptoms in cholera patients.