Tag Archives: GPCRs binding to each other

Another neuropharmacologic surprise.

Our genome contains 826 different genes for G Protein Coupled Receptors (GPCRs) which are targeted by at least 475 FDA approved drugs (Nature vol. 587 p. 553 ’20 ). Yet part of the fascination of reading the current literature is the surprises it brings.

Our basic understanding was that the GPCRs sit on the surface of the cell waiting for ligands outside the cell to bind to it, which produces a conformational change on the cytoplasmic side of the cell membrane, changing the way the GPCR binds to the G protein, triggering all sorts of effects inside the cell.

As far as I recall, we never thought that different GPCRs would bind to each other in the cell membrane, even though a single cell can express ‘up to’ 100 different GPCRs [ Mol. Pharm. vol. 88 pp. 181 – 187 ’15 ].  Neurons express GPCRs and some are thought to be involved in neuropathic pain

But that’s exactly what Proc. Natl. Acad. Sci. vol. 119 e2123511119  ’22  is saying.

First a few definitions, if you’re as rusty about them as I was

A cytokine is an extracellular protein or peptide  helping cells to communicate with each other.  A chemokine is an extracellular protein which attracts cells.

Our genome has over 50 chemokines.  Most are  proteins with about 70 amino acids. The are classified by where the cysteines lie in them.  We have 23 receptors for chemokines, 18 of which are GPCRs.   Binding is promiscuous — a given chemokine binds to multiple receptors, and a given receptor binds to multiple chemokines.

Clearly the chemokines and their receptors are intimately involved in inflammation which always involves cell migration.  Neurons express chemokine receptors GPCRs and some are thought to be involved in neuropathic pain.

We also know that the nervous system is involved in immune function, particularly inflammation.  One prominent neurotransmitter is norepinephrine, and a variety of receptors bind to it.  There are 3 alpha1 norepinephrine receptors (a, b and d), all of which are GPCRs.

What is so shocking is that alpha1 GPCRs bind to chemokine receptors (forming heteromers), and that this binding is required for chemokines to have any effect on cell migration.  Even more interesting is that binding of norepinephrine to the alpha1 component of the heteromer INHIBITs cell migration.

So how many of our 826 GPCRs bind to each other, and what effects do they have?

Reading the literature is like opening presents, you find new fascinating toys to play with, some of which may actually benefit humanity