Receptor desensitization, downregulation and upregulation

Receptor desensitization starts with one idea: receptors are not fixed

A man with asthma uses his inhaler exactly as before, but each puff helps a little less. The drug has not changed and neither has his dose. One answer is his receptors.

This lesson covers receptor desensitization and its relatives: tachyphylaxis, downregulation and upregulation, and the clinical trap they set when a drug is stopped suddenly.

A receptor is not fixed furniture. A cell adjusts how many receptors it displays, and how well they signal, to match the signal it is getting.^[1][14]

The example receptor: beta-2, Gs and cyclic AMP

Take the beta-2 receptor. It is coupled to Gs, which activates adenylyl cyclase, so cyclic AMP rises.^[2][1]

Everything below is about what happens to this signalling when an agonist or an antagonist stays on the receptor for a long time.

Desensitization and tachyphylaxis: GRK and beta-arrestin

Keep an agonist on the receptor and a kinase called GRK soon phosphorylates the occupied receptor. Beta-arrestin then binds to it.^[3][1]

Arrestin blocks the G protein from coupling, and the receptor is often pulled inside the cell. The cell is deaf to the drug, though the receptor is still there. That is desensitization.^[3][1]

When the response falls rapidly with repeated or continuous dosing, we call it tachyphylaxis.^[4][5][6]

1. Agonist occupies the receptorThe receptor signals through Gs.
2. GRK phosphorylates itGRK targets only the agonist-occupied receptor.
3. Beta-arrestin bindsThe G protein can no longer couple, and the receptor is often internalised.

Downregulation: fewer receptors after chronic agonist

Keep the agonist there longer and the cell goes further: receptors are degraded, and fewer are made. That is downregulation: fewer receptors.^[1][14]

Recovery is slow, because it needs new receptors to be built.^[1]

Chronic beta-agonist exposure does this to beta-2 receptors, which is our asthma patient: the bronchodilator response falls.^[1][6]

Upregulation: more receptors after chronic antagonist, and the rule

Now reverse it. Block a receptor for a long time, and the cell hears silence. It answers by building more receptors. That is upregulation.^[1][14][7]

Beta-blocker withdrawal: why the extra receptors matter

Picture a heart cell with forty beta receptors. This is an illustration, not a measurement. Under a beta-blocker, the cell builds up to, say, sixty. While the drug is on board, the blocker masks the larger receptor pool.^[7][14]

Now stop the drug. The same norepinephrine now meets fifty percent more receptors, and the response is exaggerated.^[14][7]

That is beta-blocker withdrawal: rebound tachycardia and palpitations, sometimes high blood pressure, and arrhythmias in some patients. The usual explanation is that chronic blockade raised receptor density.^{[7][8][9][11]}

The catecholamine level does not need to be high; it is the sensitivity that is raised.^{[7][8][9][10]}

So beta-blockers are tapered, not stopped abruptly.^[8][15]