Question 1Multiple choiceCell communication & signal transduction
Epinephrine binds to a G protein-coupled receptor on liver cells, activating a G protein that switches on adenylyl cyclase. The resulting rise in cAMP activates protein kinase A, which ultimately promotes glycogen breakdown. A liver cell carries a mutation in the alpha subunit of this G protein that prevents it from hydrolyzing GTP but does not affect GTP binding. After a brief exposure to epinephrine that is then washed away, which outcome is most likely in the mutant cell compared with a normal cell?
- A.
Adenylyl cyclase stays active and cAMP remains high, so glycogen breakdown continues long after the epinephrine is gone.
- B.
No cAMP is produced, because the G protein cannot be activated without GTP hydrolysis.
- C.
The receptor can no longer bind epinephrine, so the pathway is never switched on.
- D.
The response is identical to that of a normal cell, because GTP hydrolysis only recycles GDP and does not affect signalling.
Worked solution
Work through what GTP binding and GTP hydrolysis each do in a G protein cycle. In the resting state the alpha subunit holds GDP and is inactive. When epinephrine binds the receptor, the receptor causes the alpha subunit to release GDP and bind GTP; the GTP-bound alpha subunit is the active form that stimulates adenylyl cyclase. The G protein is also its own timer: its built-in GTPase activity hydrolyzes the bound GTP to GDP after a short time, which switches the signal off. Washing away the ligand only stops new activations; G proteins that are already active are shut down by hydrolysis.
In the mutant, GTP binding (activation) is normal, so the pathway turns on as usual. What is lost is the off switch. The alpha subunit stays locked in the GTP-bound, active state, so adenylyl cyclase keeps converting ATP to cAMP, protein kinase A stays active, and the downstream enzymes keep breaking down glycogen even though the hormone is no longer present.
The signal cannot be terminated: cAMP stays elevated and glycogen breakdown continues after epinephrine is removed (option A).
Option B is the most common confusion; it mixes up the two steps. Hydrolysis is what turns the G protein off, not on, so blocking it cannot prevent activation. Option C is wrong because the mutation is in the G protein, not the receptor, so ligand binding is unchanged. Option D ignores that hydrolysis is the only way the active alpha subunit returns to its GDP-bound state; without it the response is prolonged, which is the same mechanism by which cholera toxin causes persistent cAMP signalling in intestinal cells.