Tag Archives: norepinephrine

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


Why don’t serotonin neurons die like dopamine neurons do in Parkinson’s disease

Say what ?  “This proportion will likely be higher in rat dopaminergic neurons, which have even larger axonal arbors with ~500,000 presynapses, or in human serotonergic neurons, which are estimated to extend axons for 350 meters” – from [ Science vol. 366 3aaw9997 p. 4 ’19 ]

I thought I was reasonably well informed but I found these numbers astounding, so I looked up the papers.  Here is how such statement can be made with chapter and verse.

“The validity of the single-cell axon length measurements for dopaminergic and cholinergic neurons can be independently checked with calculations based on the total volume of the target territory, the density of the particular type of axon (axon length per volume of target territory), and the number of neuronal cell bodies giving rise to that type of axonThese population analyses are made possible by the availability of antibodies that localize to different types of axons: anti-ChAT for cholinergic axons (also visualized with acetylcholine esterase histochemistry), anti-tyrosine hydroxylase for striatal dopaminergic axons, and anti-serotonin for serotonergic axons.

The human data for axon density and neuron counts have been published for forebrain cholinergic neurons and for serotonergic neurons projecting from the dorsal raphe nucleus to the cortex, and cortical volume estimates for humans are available from MRI analyses; forebrain cholinergic neuron data is also available for chimpanzees. These calculations lead to axon length estimates of 107 m and 31 m, respectively, for human and chimpanzee forebrain cholinergic neurons, and an axon length estimate of 170–348 meters for human serotonergic neurons.”

H. Wu, J. Williams, J. Nathans, Complete morphologies of basal forebrain cholinergic neurons in the mouse. eLife 3, e02444 (2014). doi: 10.7554/eLife.02444; pmid: 24894464

How in the world can these neurons survive as long as they do?

Not all of them do–  At birth there are 450,000 neurons in the substantia nigra (one side or both sides?), declining to 275 by age 60.  Patients with Parkinsonism all had cell counts below 140,000 [  Ann. Neurol. vol. 24 pp. 574 – 576 ’88 ]. Catecholamines such as dopamine and norepinephrine are easily oxidized to quinones, and this may be the ‘black stuff’ in the substantia nigra (which is latin for black stuff).

Here are the numbers for serotonin neurons in the few brain nuclei (dorsal raphe nucleus) in which they are found.  Less than dopamine.  A mere 165,000 +/- 34,000 — https://www.ncbi.nlm.nih.gov › pubmed

So being too small to be seen with a total axon length of a football field, they appear to last as long as we do.  Have we missed a neurological disease due to loss of serotonin neurons?

Why should the axons of dopamine, serotonin and norepinephrine neurons be so long and branch so widely?  Because they release their transmitters diffusely in the brain, and diffusion is too slow, so the axonal apparatus must get it there and release it locally into the brain’s extracellular space, no postsynaptic specializations are present in volume neurotransmission — that’s the point.  This is one of the reasons that a wiring diagram of the brain isn’t enough — https://luysii.wordpress.com/2011/04/10/would-a-wiring-diagram-of-the-brain-help-you-understand-it/.

Just think of that dopamine neuron with 500,000 presynapses.  Synthesis and release must be general, as the neuron couldn’t possibly address an individual synapse.

The more we know the more remarkable the brain becomes.