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Purinergic Signalling and CNS Disorders by Professor Geoffrey Burnstock

Jo Best

Senior Member
Messages
1,032
This is a presentation from the 6th Invest in ME Research international conference in 2011 (IIMEC6) so it's not new, but I had not seen it before as I don't have the IIMEC6 DVD set. I will have to watch it over a few times over to take it all in, but am sharing here now while I have the link handy in case it's of interest to anyone else. Source of extract below: http://www.investinme.org/IIMER-Newslet-17-08-01.shtml

IIMEC6: Purinergic Signalling and CNS Disorders

PROFESSOR GEOFFREY BURNSTOCK

Our annual international conferences and research colloquiums are designed to bring together researchers, clinicians, patient groups and patients/carers in order to make progress in research into ME.

Invest in ME Research has, for years, also sought to bring in researchers from other fields in order to help expedite progress in research into ME and to utilise the best minds available.

In 2011 IiMER invited Professor Geoffrey Burnstock to our conference events. IIMEC6 was the 6th Invest in ME International ME Conference arranged and hosted by the charity and held in London.

At this time we thought it appropriate to release his presentation at the IIMEC6 conference.

The title of his presentation was -

Purinergic Signalling and CNS Disorders

Professor Burnstock has published over 1400 papers and supervised 100 PhDs so he is quite an expert.

" Professor Geoffrey Burnstock studied theology, maths and physics at King's College London, before completing a PhD at King's and University College London under the supervision of the neurophysiologist, JZ Young. Between 1959 and 1975, Professor Burnstock worked at the University of Melbourne, beginning with a senior lectureship in zoology. Most of his major research has been on the autonomic nervous system, notably autonomic neurotransmission and he is best known for his discovery that ATP is a transmitter in NANC (non-adrenergic, non-cholinergic) nerves and also for the discovery and definition of P2 purinergic receptors, their signaling pathways and functional relevance.

Professor Burnstock's work in this area has had an impact on the understanding of pain mechanisms, incontinence, embryological development, bone formation and resorption, and on skin, prostate and bladder cancer. Professor Burnstock returned to London in 1975, becoming Head of Department of Anatomy and Developmental Biology at University College London and Convenor of the Centre of Neuroscience.

He has served as editor-in-chief of the journals Autonomic Neuroscience and Purinergic Signalling and has been on the editorial boards of many other journals. He has been elected to the Australian Academy of Science, the Royal Society and the Academy of Medical Sciences, and was awarded the Royal Society Gold Medal in2000. He was President of the International Society for Autonomic Neuroscience (ISAN), and was first in the Institute of Scientific Information list of most cited scientists in Pharmacology and Toxicology. (from The UCL Centre for the History of Medicine)"

From http://publizr.com/investinmeresearch/journal-of-iime-vol-5-issue-1/54?html=true#/55/

Source: http://www.investinme.org/IIMER-Newslet-17-08-01.shtml



 
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Jo Best

Senior Member
Messages
1,032
Not specific to ME or CFS research, but a lot that resonates in this interview with Geoff Burnstock.
Published on Aug 30, 2013.
Professor Geoffrey Burnstock's personal philosophy of 'if you can't do it one way, you find another' saw him transition out of graveyard work to studying theology, maths, physics and biology at university. He reflects on a star-studded career in autonomic neuroscience and gastroenterology, the importance of a creative spirit and his first ever in vivo motility publication which involved the tricky business of putting condoms on fish.

 
Messages
80
cliffs of what seems worth mentioning to to me:
- on the 'p2 receptor antagonists' slides, suramin is mentioned several times.
- methylxanthines (caffeine, theobromine etc) are p1 antagonists. adenosine and adenosine monophosphate (which might accumulate when ATP synthesis is slowed down) are the stronger agonists of these receptors.
- p2 has the reverse affinity order, i.e. ATP and ADP are the most potent agonists. so maybe some underactivation is in play (probably keeping in the back of one's head that this does not have to be a systemic effect or a very strong effect all the time)
- the 'main sources of ATP' slide mentions at lot of different cell types that have been mentioned in the ME literature at one point or another
- release of ATP from endothelial cells and a subsequent signaling cascade leading to release of NO (-> vasodilation) is a very integral part of a functioning vascular system
- the stuff from ~ minute 15 on about ischemic and neuropathic pain seems relevant as well, but is over my head right now and I can't really shorten it in meaningful way ;)
 

anciendaze

Senior Member
Messages
1,841
...
- release of ATP from endothelial cells and a subsequent signaling cascade leading to release of NO (-> vasodilation) is a very integral part of a functioning vascular system...
I want to mention that this process is not entirely inside any nervous system. Endothelial cells can respond to nerve signals, but they can also respond to local hypoxia by releasing ATP to help cells survive via anaerobic metabolism. Another major source of ATP in regions of localized hypoxia comes from red blood cells (erythrocytes), after they have released oxygen they carry. Since these cells spend most of their time in other regions of the body, they have considerable capacity to generate new ATP which can be released later. This could be the answer to contradictions about amounts of ATP, and whether mitochondria are creating it. We could be looking at the wrong cells, or assuming all cells are functioning the same way.

This response to exercise, called functional sympatholysis or exercise hyperemia, is a normal means of supplying increased oxygenated blood to muscles that require it. You are most likely to find the term in sports medicine. It is rare for defects in this process to be described as actual illness. Usually, this is mentioned as a condition associated with more conventional diseases not as a cause. Here's an exception. The idea that defects in this process may trap patients in a situation where exercise leads to reduced capacity for several days has yet to make much headway.

A large subset of us seem to be stuck in the phase of vasodilation along venous return to the heart, leading to low cardiac fill pressures. Customary measurements of cardiovascular health will miss this, but there is an invasive cardio-pulmonary exercise test that will find it.
 

mariovitali

Senior Member
Messages
1,214
Giving my two cents here :

From the paper named "The role of nucleotides and purinergic signaling in apoptotic cell clearance – implications for chronic inflammatory diseases " we read :

The interaction between dying cells and phagocytes is very complex and nucleotides have been involved in orchestrating the process of dead cell removal. On the one hand, nucleotides and purinergic signaling have been shown to play a key role in the apoptotic cell clearance avoiding secondary necrosis, preventing inflammation and contributing to regeneration of injured tissues. On the other hand, purinergic signaling over-activation is involved in chronic inflammation and chronic inflammatory dis- eases.


But also interesting is the mention of GAS6 in the same paper


The recognition of apoptotic cells can also be mediated indirectly via bridging molecules or accessory receptors, such as MFG-E8, the C-reactive protein, and Gas-6 (52, 53). Engagement of the PS receptors initiates signaling events within the phagocytes that lead to activation of the small GTPase Rac, and subsequent cytoskeletal reorganization, which ultimately leads to engulfment of the apoptotic cell

I now plug in "purinergic_receptor" on the Feature Selection Algorithm to uncover any indirect associations on Purinergic functioning and get this :

suramin.png



The tool identifies Suramin, nucleotides, calcium homeostasis, inflammatory_cytokines but also things that perhaps are less well known (GAS6 is also selected but not shown below):

-Intestinal motility
-Vitamin B6
-Vitamin D3
-Vitamin K
-VKORC1

The association of Purinergic receptors with these Topics may require further investigation.
 

anciendaze

Senior Member
Messages
1,841
I just want to add some appreciation of scale here. A great deal of biochemical signalling takes place at nerve synapses, where the molecules only travel micrometers between release and reception. When purines like ATP, ADP, etc. are released into the bloodstream they can travel several centimeters or more before they reach receptors on endothelial tissue inside blood vessels. The scale is many thousands of times greater. This is on the scale of individual muscles, but still much smaller than the scale of your whole body. Measurements of O2sat will not show much change because most tissues in your body are not hypoxic. This doesn't rule out localized hypoxia due to hypoperfusion.

Another chemical signal for vasodilation involves NO, nitric oxide. I remember my surprise, long ago, when this was first reported as a neurotransmitter. From experience in chemistry I know that this is a very reactive molecule, and I had been taught (incorrectly) that the chemicals used in biochemistry were much less reactive. This property makes NO difficult to work with in normal clinical laboratory practice. There have been some very delicate experiments in which tiny tubes were threaded through a patient's skin, and these showed differences in NO release between ME/CFS patients and healthy people. For the most part we don't even know how purinergic signalling and NO release operate in people like athletes, where it works very well.

A recent search turned up more recent research than I had seen at an institute in Copenhagen, Denmark. Several other molecules mentioned here, like NA (noradrenaline) or ROS (reactive oxygen species) are on my list of interest. Anything to do with sympathetic nervous system activity and muscles will also pique my interest.