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My understanding is that if a cell is flooded with a certain neurotransmitter, it may decrease the density of that neurotransmitter. What I don't understand is how.

Is it a direct physical result of the receptor-ligand complex being internalized? I.e., the receptors simply aren't there anymore, because they've been internalized?

Or, does the internalization of specific receptor-ligand complexes actually get sensed by the cell somehow, causing it to produce fewer receptors in the future?

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Both internalization (sometimes with degradation) and changes in gene expression can occur; the circumstances leading to the down regulation determine which (or both). It isn't necessary for receptors to be bound to their ligand to be internalized, though, and it isn't the internalization of receptors that causes changes in gene expression (I suppose it is possible that happens someplace, but not that I am familiar with). The processes involve activation of second messenger systems and kinases that either phosphorylate/dephosphorylate the receptors to mark them for internalization and/or degradation, or activate/deactivate transcription factors.

Here are two reviews with more information: one is newer but focused on a single class of receptors and fairly in-depth; the other is a bit dated but more broad, but brief:

Williams, J. T., Ingram, S. L., Henderson, G., Chavkin, C., von Zastrow, M., Schulz, S., ... & Christie, M. J. (2013). Regulation of µ-opioid receptors: Desensitization, phosphorylation, internalization, and tolerance. Pharmacological reviews, 65(1), 223-254.

Tsao, P., & von Zastrow, M. (2000). Downregulation of G protein-coupled receptors. Current opinion in neurobiology, 10(3), 365-369.

You can also read about long term depression, which is different from homeostatic responses to ligand concentrations, but it does seem to serve a homeostatic function to keep overall synaptic strengths from growing indefinitely, and the molecular pathways are very similar (and it is a very well-studied phenomenon so you will find a lot of accessible information).

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  • $\begingroup$ > internalization of receptors that causes changes in gene expression EGFR translocation to the nucleus was an example that came to mind (ref). $\endgroup$ – CKM May 9 '17 at 20:14
  • $\begingroup$ @CMosychuk Thanks for the comment, it's a good opportunity for a clarificaiton. Yes of course, there are receptors for which internalization itself (after binding a ligand) is a signalling mechanism. I was referring only to the homeostatic regulation of membrane receptor concentrations in response to excess ligand, as in the OP. I wouldn't consider receptor internalization as part of a regular signalling pathway to be part of that homeostatic regulation. But thank you for pointing out that internalization can be a signal, I didn't mean to imply that it isn't elsewhere. $\endgroup$ – Bryan Krause May 9 '17 at 20:20

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