Receptor upregulation and downregulation · Lobeworks/17

Receptor upregulation and downregulation are the processes by which a cell raises or lowers the number of a receptor it displays, or how readily that receptor responds, so that its sensitivity to a signal follows how much of that signal it has been getting.

Receptor upregulation and downregulation. Receptor upregulation and downregulation are the processes by which a cell raises or lowers the number of a receptor it displays, or how readily that receptor responds, so that its sensitivity to a signal follows how much of that signal it has been getting.

A cell has three dials. On a timescale of minutes it moves receptors already made: binding by an agonist can tag a receptor for removal from the membrane by endocytosis (internalisation), after which it is recycled or destroyed, while stores of receptors inside the cell can be inserted into the membrane. Over hours it changes how receptors are switched by phosphorylation (desensitisation). Over days to weeks it changes how many it makes, by gene expression. At a synapse the fast dial is the expression of learning: long-term potentiation inserts AMPA receptors into the spine, and long-term depression pulls them out by endocytosis.

Too much signal turns the cell down. Chronic exposure to an agonist tends to desensitise and remove its receptors, which is the cellular basis of much drug tolerance: the same dose produces less effect, and stopping it leaves a cell set for a signal that is no longer there, felt as withdrawal.

Too little turns it up. Chronic blockade or absence of the ligand tends to raise receptor numbers and make cells supersensitive. Long blockade of D2 dopamine receptors by older antipsychotics upregulates them in the striatum, the leading (and incomplete) explanation of the late movement disorder tardive dyskinesia.

It is one reason drugs acting on receptors take time. A drug's first effect is on the target it binds; the adaptations of receptor numbers and signalling that follow over weeks are part of what the brain ends up with, and for some drugs part of how they work.

A cell keeps its sensitivity proportional to what it expects.

Flood it and it removes receptors; starve it and it adds them, so the effect of any steady signal, a drug included, fades back towards normal.

Questions: How does long-term potentiation show up as more AMPA receptors? Calcium entering through NMDA receptors switches on the enzyme CaMKII, which makes the AMPA receptors already in the synapse conduct more and helps drive extra receptors, held in stores inside the spine, into the membrane and trap them there. The synapse is stronger because the same puff of glutamate now opens more channels. It is receptor upregulation on a timescale of minutes, and long-term depression runs it backwards, pulling receptors out by endocytosis. Why does a drug acting on a receptor lose part of its effect with repeated use? Because cells adjust their receptors to the signal they keep receiving. A drug that keeps activating a receptor drives its desensitisation and removal, so the same dose produces less, which is tolerance, and stopping it leaves too few receptors for the normal signal, felt as withdrawal. A drug that keeps blocking one does the reverse: long blockade of D2 dopamine receptors by older antipsychotics raises their number in the striatum, the leading explanation of the late movement disorder tardive dyskinesia.