Cholera toxin is an enzyme that covalently modifies the \(G_{\alpha}\) -subunit of G proteins. (Cholera toxin catalyzes the transfer of ADP-ribose from NAD \(^{+}\) to an arginine residue in \(G_{\alpha},\) an ADP-ribosylation reaction.) Covalent modification of \(\mathrm{G}_{\alpha}\) inactivates its GTPase activity. Predict the consequences of cholera toxin on cellular cAMP and glycogen levels.

G proteins play a pivotal role in transmitting signals from outside the cell to its interior. Think of these proteins as the cell's communication relay team. The G protein is typically in an inactive state when bound to a molecule called GDP (guanosine diphosphate). But, when a signal arrives, it exchanges GDP for GTP (guanosine triphosphate), becoming active.

This active state kicks off a series of cellular events. However, the G protein isn't meant to stay active indefinitely. It has a built-in 'off switch', a GTPase activity that converts the GTP back to GDP, which turns the protein off.

Cholera toxin sneaks into this system and jams the 'off switch' by modifying the G protein in such a way that it can no longer convert GTP back to GDP. As a result, the G protein remains in a constant state of alert, passing on endless signals that result in various physiological effects, one of which involves the production of cAMP.

One of the main signals that an active G protein transmits involves the production of cAMP (cyclic adenosine monophosphate), a second messenger with many cellular roles. Typically, the G protein activates an enzyme called adenylate cyclase, which converts ATP (adenosine triphosphate) into cAMP.

With cholera toxin in play, adenylate cyclase remains uninhibited due to the G protein's perpetual active state, resulting in a surge of cAMP production. This increase in cAMP orchestrates a cascade of downstream effects that impacts processes like glycogen metabolism. The high cAMP levels essentially push the cell's activities into overdrive, which can disrupt the normal balance and functions within the cell.

The concentration of cAMP has a direct effect on glycogen metabolism. Glycogen is a stored form of glucose, which is used as an energy source. When cAMP levels rise, they activate an enzyme named protein kinase A (PKA).

PKA sets off a chain reaction: it activates phosphorylase kinase, which in turn activates glycogen phosphorylase, the key player in breaking down glycogen into glucose-1-phosphate. The rise in cAMP caused by cholera toxin-induced G protein activity would therefore lead to an increase in the conversion of glycogen to glucose. This uncontrolled breakdown can deplete glycogen reserves, alter blood sugar levels, and cause energy imbalances in affected cells.

The sneaky move used by cholera toxin to hijack cell signaling is known as an ADP-ribosylation reaction. In this biochemical trickery, cholera toxin transfers ADP-ribose, a component part of the energy-carrying molecule NAD+, to an arginine residue on the G protein's alpha subunit.

This transfer fundamentally alters the structure of the G protein, impeding its ability to perform its normal 'switching off' duty. Essentially, cholera toxin sticks a molecular wedge in the G protein's GTPase activity, preventing it from converting GTP back to GDP. This sabotage results in the continuous activation of the signaling pathway and the unregulated production of cAMP, which, as we've seen, leads to a cascade of reactions including the disruption of glycogen metabolism.