Turning Off Beta Adrenergic Signaling

Clinical Relevance 💡

Cholera causes Gas to be stuck in the “on” position. This means that the signaling does NOT get shut off (See regulatory step #2). As a result, it causes the loss of mass amounts of water and NaCl into the intestine.
This leads to excessive diarrhea which is characteristic of cholera. This is so dangerous as this excessive water loss can be fatal due to dehydration.

Notes

As a quick review of the beta pathway:

Glucagon or Epinephrine bind to the receptor
The G-protein subunit undergoes a conformational change that causes it to RELEASE GDP and bind GTP.
Gas (alpha subunit and GTP) is formed by the dissociation of the beta and gamma subunits→ this just leaves the alpha subunit and GTP
Gas binds to adenylate cyclase
cAMP is cyclized
cAMP then binds protein kinase A (PKA)

RESULT: Glycogen breakdown→ get a release of glucose!

To stop the signal from going on indefinitely, the signal must be terminated.

Ligand dissociates from the receptor. If the ligand is no longer bound, it is not in the “active” state anymore (This "reverses" #1)
However, the alpha subunit is still bound to adenylate cyclase. Therefore, to turn it off, the GTP must be converted back to GDP, and the other two subunits must come back and bind to the alpha subunit.
Next, cAMP needs to be decyclized to stop amplifying the message. This is done by phosphodiesterases.

To remember this, keep in mind that cAMP is made from ATP which has a lot of phosphate groups, and since it wants cAMP to stop working its going to make it die. → phosphodiesterases

Note, it's not scientific, but if it helps you remember, it can’t hurt.

Lastly, phosphatases remove phosphate groups from target proteins that were added by PKA.

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