Monday, January 18, 2010

ATP as Neurotransmitter

ATP as Neurotransmitter
Andre Willers
18 Jan 2010

Synopsis :
ATP has been proven to be a neurotransmitter . Various receptor sites on cellwalls have been found as result of the Human Genome project . Important health considerations result .

Discussion :
See important article in ScientificAmerican Dec 2009 , p60 "The double life of ATP" by BS Khakh and G Burnstock (let us hope that nominative determinism does not hold sway .)
Beg , borrow , steal or buy a copy .

See "ATP and Catalytic Motors" . Appended in Appendix A for ease of reference .

Crackpot duckling into Swan :
The effect had been clinically demonstrated since 1959 , but disregarded as not fitting into the accepted model .
The isolation of certain ATP and ADP receptors in 1993 and 1994 , as well as development of Clopidogrel to prevent clot formation led to greater acceptance .
The Human Genome Project led to the genes for receptor sites of ATP and it's various breakdown products . It is now a Hot Subject (ie fashionable) . A number of drugs are in various development stages .
A lot of money , major health items and knowledge is in play .

A Brief Description .
It is a very elegant mechanism . Also very old .

1. ATP = Adenosine + P + P + P
= AdenosineTriPhosphate
2. ABP= AdenosineBiPhosphate (the last phosphor atom has been stripped away . This is energy bond powering the muscles)
3. AMP= AdenosineMonoPhosphate . Only one phosphor atom .
4. Adenosine is adenosine (a purine) without any phosphor atoms .

Every cell has specialized receptor sites on the surface that interacts with one or a combination of these compounds . This gives at least 2^4=16 possible basic receptor types .
See "Phene Systems"

The information being triggered is in the cell-wall (the Phene system) . This causes various portals to open or close , influencing sodium , calcium , etc balances in cellular substructures (including DNA in the chain)
See "Unpacking and packing information"

Surrounding the cells are class of enzymes called EctoATPases that sequentially strip away the phosphor atoms from ATP .
See "Chaperones , unpacking and asthma"

This stripping of phosphor atoms makes the whole system workable by creating four unique markers necessary and sufficient for a three dimensional contiguous information space.

A teensy little problem is : where does all this energy go ? Heating up the synaptial fluid seems to be a result . Is this essential for multi-cellular life ? The intercellular information transfer spaces are then always hot and ready to roll . Certainly , it would give a great advantage to even a cold-blooded lifeform . The energy costs would not be very high .

From an evolutionary viewpoint , it is easy to see that a temperature control mechanism in synaptial fluids expanded into the whole organism in a random mutational-selection process .

But what is the original mechanism ?
See ApendixA "Throttle"
It must involve the production speed of ATP : ie the rotational speed of the rotor in the mitochodria .
There are two known ways to influence this:
Ironically , sleep seems to be basically necessary to give synaptical spaces a chance to cool down . If they grow too hot , the other neurotransmitters start breaking down and the well-known dementia of sleeplessness results . Obviously , the immune system is affected as well . This whole ATP signaling system is part of the immune control-system .
Note the correlation of symptoms between heat-stroke , sleeplessness and forms of dementia associated with various neurotransmitter shortages .

2.APS generator .
(See AppendixA)
The pulsed waveform will not only speed up lagging mitochondrial rotors, but also slow down ones that are too fast (ie overproducing ATP) . This should ameliorate synaptial fluid overheating .
Ideally , we should have an APS generator that can force a desired spin rate on any set of organs . But the one we can buy now is set at 3 milliseconds .

Remember , a standard human produces about 40 Kg of ATP per day (See AppendixA)

An useful analogue:
Using the energy transmission conduit also as an information transmission route is used in electrical systems . You can buy a system that uses the electrical wiring of your home to transmit music , video , internet , etc .
The analogue goes both ways , since the problems with the electrical system will also be experienced in the ATP system .

Known systems using ATP as neurotransmitter:
1.Blood vessel constriction : ATP as co-neurotransmitter with noradrenaline .
2. Blood vessel dilation : shear stress->ATP->NO->vessel relaxation.Part of the feedback system .
3.Blood clotting: platelets have ADP receptors.
4.Cell proliferation : eg restinosis , various cancers . See Phene control system .
5.Eye: acetylcholine and ATP are co-neurotransmitters.
6.Ear :about 50% of cochleal hairs have ATP receptors.
7.Taste:as expected , evolutionary old chemical receptors like taste or smell do not function without ATP receptors(in this case P2X2 and P2X3 receptors) .
8.Pain and touch: mainly the P2X3 receptor .
9.Neuropathy :
See "Neuropathy"
P2X receptors are involved .
10.Digestive system:
Irritable bowel syndrome and Crohn's disease :P2X and P2Y receptors are involved .
11.Clotting :
Existing drugs Clopidogrel and Prasugrel blocks P2X12 receptor .
12.Tumors , developmental diseases , etc .
13.Disease regulation using bacterial ATP signaling.
14.Old Age
Apoptosis and ATP quorum mechanisms await exploration .

The Phene System:
It seems that the ATP signaling systems plays an important part in the meta-control system of multi-cellular organisms (multi-cellular includes a single cell with a mitochondrium by definition) .

We know that viruses encapsulated by cell-wall material is the signaling mechanism of cells .

Speculation : Distributed Viruses .
That ATP , ADP , AMP and Adenosine plus receptor sites form a distributed virus
The crystal structure of the P2X receptor looks like a typical virus . It only needs the key(s) to activate . As expected from a phene control mechanism , it regulates activities in the cell via switching on or off of genes in the DNA .
(See how handy the concept of phenes is ?)

Even more speculative :
Do not try this without qualified supervision .
Diseases like AIDS , cancer or old age must interact with the ATP signaling system at some stage . Quorum systems play a role (why we use melatonin)
Slow down the mitochondrial rotors with melatonin , and simultaneously entrain them with a APS generator on selected organs . Pulse if necessary .
This will hopefully break interlocked feedback cycles .

Interestingly , this should work on fevers as well , as well as disrupt quite a few viral diseases .

A hot time in the old town tonight .

Andre .


Appendix A

ATP and Catalytic Motors
Andre Willers
4 Dec 2008

The Catalytic Motor.
See Annexure A below .
This is a new concept to me .

The basic principle :
The chemical equilibrium of a reaction is biased in a certain direction by dynamical , rotational processes .

And not in a trivial way either . A whopping 40 kg per day production and consumption of ATP for a sedentary human (of say mass 80 kg) means a very finely balanced mechanism . (Half of body mass per day)

The logistical demands almost necessitate a multi-cellular organism .

Where does the rotor come from ?
From bacterial flagellae . They work by rotation of the flagella .(Google it)
The rotor is driven by proton gradients , caused by electron-flow balances between inflowing nutrients and usage .

Putative evolution :
The ur-mitochondrium was a free organism whose flagellae by chance could beat two poisons (oxygen and alcohol) into harmless ATP . As if protein-folding was not complicated enough , now dynamics have to be considered as well .
As the concentrations of these poisons increased , ur-mitochondria did the usual plaque - freeform alternation of bacteria . In every colony episode , the efficiency of the conversion was enhanced . At some stage , a freeform colonized some other bacterium . The host learned to use ATP as an energy source . Multicellular forms were force-formed .
The motors of the mitochondria cannot stop spinning . (If they do , apoptosis results: see Appendix B) . The ATP has to be used .

Rotor-spin speed:
This seems to be quite slow . (As expected from a flagella heritage) . About one to three milliseconds per revolution . ( About 1 to 0.3 kHz) . The ATP production is not smooth either . There are three units physically opening and closing (see Appendix A).

A very useful analogue:
We can use an national electricity grid operating at 1 kHz alternating current of three-phase current as an tool for understanding the meta-energy flow in the body . Every cell would be like a municipality with its own powerstation .
The voltage and transformers ? Nobody has looked , but a guess would be ATP concentration regulators , like the reticular cellular formations , antioxidants (see Appendix B) , ATP chaperones , cellular-wall ports , etc . You get the drift .

The advantage of this approach is that we then have an immediately usable box of tools to analyze and suggest fruitful new approaches .
Our electricity networks would also gain , since evolution has been at this problem for a tad longer than humans .

Melatonin for ESKOM ? Some would say they are asleep at the switch in any case .

Throttles .
There seems to be a wee problem here .
The problem seems to be too much energy , not too little .
Most organisms normally spend 1/9 to 1/3 of 24 hours actually getting enough to eat . The rest is spent having fun or sleeping .
But a certain reserve needs to kept (see "Infinite Probes" et al )

There is a strong suspicion that melatonin throttles down the production of ATP , but not the usage of ATP (cf fMRI scans of sleeping brains) See Appendix B . Sleep would then be necessary to keep the organism out of trouble (ie quiescent) while surplus ATP is used up . (1/3 : eg 8 hours per day)

Obesity epidemic:
As can be seen from the above , the problem is not a sudden influx of energy-rich food .This has been a trouble since the first mitochondrium took up housekeeping in a host cell .
The obesity is caused simply by a lack of sleep .
Present generations sleep less . Artificial lighting , computers , cinema , etc . The extra waking time is also usually spent eating .
The equilibrium is upset . (This has been going on for about 100 years on a large scale) .

An interesting result is the generational increase in IQ measurements . The system is trying to soak up the extra energy in more complex nervous structures (for which it has the evolutionary tools) . An epigenetic feedback loop is suspected .

Kids who stay up late for three generations will be fatter and smarter .

Diabetes .
Melatonin has many effects . Lack of it causes neuro-degenerative complications (see Appendix B) . Included is peripheral neuropathy . This is where we can use our useful little model of an electricity grid above . Without the feedback from the damaged nerves , the system cannot shift loads . Just monitoring the glucose level is too coarse. Fluctuations build up . Future load estimations cannot be made . Fat builds up .

Old Age
Lack of sleep during old age leads to glucose metabolic complications for all the reasons mentioned , regardless whether the person is obese or not .

Other throttles are rendered less effective by lack of materials:
Specifically , sulfur (H2S hibernation throttle) , chrome (cytochrome oxidase : see Appendix B) , alpha lipoic acid(nerve repair) , melatonin .

Homeostasis is another useful little energy soak .
Large brains ditto .

But Culture , hot or cold , is master of them all .
Nothing soaks up energy like culture . Fashion is by far the largest industry on the planet , outstripping even food production .
Eg sports is a fashion . Clothes .Entertainment . Tourism . Even lies . (JK Rowling is the most fashionable and richest professional liar in Britain .)

What is the culture of your mitochondria ?

An Actual , Physical ATP generator you can buy .
This is a well-known and clinically proven machine usually touted for pain-relief .
It works .
But the theory is rather patchy . There used to be a lot of mumbo-jumbo about the gate theory of pain .

It actually works by alleviating the underlying causes of the pain (see scans on website) . It does this by pumping energy into the ATP-rotors from the outside at the damage site .

It does this by sending 3-millisecond square pulses which decay exponentially (see wave-form on web-site .) This spins up damaged rotors and transfers energy (a non-food source of energy) . Most importantly , it re-establishes timing mechanisms . Cells on the point of mitochondrial apoptosis can be salvaged . (The apoptosis mechanism is very sensitive , due to all the feedback mechanisms involved.)
While the energy input here is small , the energy of an ATP molecule is not exactly large . And the ATP is targeted exactly at the damage site . This helps to stop the cascade effect of trauma-shock .

Your attention is drawn to the well-known effects of aligned magnetic fields on bone-healing . A similar thing happens here .
Notice the effects of zero electro-magnetic fields on early astronauts .(Their metabolisms went haywire) . They had to be supplied with artificial fields .

Energise organisms directly by high-energy em-waves .
Are there any like that already ? The planet is awash with em waves and organisms with flagellae .
Deep ocean , moons of Jupiter or Saturn springs to mind .

An actual cure for diabetes by re-establishing communications between cell-groups to do proper load-sharing .
Also useful for cases of paralysis or strokes .

Fat-loss without dieting or exercising . Fashionable .
Targeted , too .
Spin up the mitochondrial rotors with em-waves , then wash out the surplus ATP in urine after fixing this ATP with something like a mono-clonal anti-body .
Get rid of that cellulite !

Cheating at sports . (Even more fashionable)
A focused em-wave of the right form will boost ATP production of an athlete or horse at that critical instant , and is nearly undetectable .

Muscle building for the gym-brigade .
Eg the machine for training the biceps can have an em-generator focused on the biceps while training . Saturation by ATP will hopefully rapidly increase muscle mass.

MRI problems .
As you will have gathered , alignment of mitochondrial rotor-spins by a powerful magnetic field as found in MRI machines can have unfortunate effects if the patient is soon afterwards exposed to em radiation of periods of 3 milliseconds (or beats thereof)

Melatonin and DHEA supplements should form part of the old age package (like statins , etc) .

Nanotech should be able to do really interesting things .

And so it goes round and round .


Annexure A
Sunday, January 21, 2007
ATP Generator Structure – Function
Almost incredibly, a sedentary adult makes and uses 40 kg of ATP per day! ATP is made by the F0-F1 ATPase, a molecular motor with a rotating shaft and fixed "stator". One end of the shaft, F0, is buried in the mitochondrial inner membrane where the proton gradient causes it to rotate. A single gamma subunit connects the F0 to three alpha and beta subunits, together F1, which are responsible for synthesizing ATP from ADP and Pi (H2PO4-). As a catalytic motor and not just a catalyst, the F0-F1 ATPase is able to increase the rate of reaction away from the equilibrium (which strongly favors the reverse reaction, hydrolysis, because the concentrations of reactants and product in mitochondria are similar). The gamma subunit rotates too slowly, in the microsecond-to-millisecond range, for standard molecular dynamics simulation. To solve this, the authors applied "biasing forces" as the motor moved and assumed these forces would not change the mechanism. Positively charged amino acids on the gamma subunit attract negative amino acids on beta subunit, producing smooth and efficient ionic coupling. Rotation of the gamma subunit induces the opening of the beta subunits. The beta subunit closes spontaneously. Synthesis is not the reverse of hydrolysis, explaining why high concentrations of free ATP does not inhibit synthesis. Gao and colleagues propose a detailed model of how the motor harnesses the proton gradient to act against the equilibrium. Their quantitative model is based on the conceptual “binding change mechanism” model proposed by Boyer, where ATP synthesis proceeds by each beta subunit changing from “open”, weak nucleotide binding, to “tight”, high affinity ATP binding, to “loose”, with the release of ATP. The authors used this model to make accurate predictions about synthesis and hydrolysis kinetics and they invite others to test their detailed model.
PubMed :Yi Qin Gao, Wei Yang and Martin Karplus, "A Structure-Based Model for the Synthesis and Hydrolysis of ATP by F1-ATPase" Cell Oct 21, 2005; 123(2):195-205

Annexure B

Melatonin, mitochondria, and cellular bioenergetics.

Acuña-Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H, Reiter RJ.

Departamento de Fisiología, Instituto de Biotecnología, Universidad de Granada, Spain.

Aerobic cells use oxygen for the production of 90-95% of the total amount of ATP that they use. This amounts to about 40 kg ATP/day in an adult human. The synthesis of ATP via the mitochondrial respiratory chain is the result of electron transport across the electron transport chain coupled to oxidative phosphorylation. Although ideally all the oxygen should be reduced to water by a four-electron reduction reaction driven by the cytochrome oxidase, under normal conditions a small percentage of oxygen may be reduced by one, two, or three electrons only, yielding superoxide anion, hydrogen peroxide, and the hydroxyl radical, respectively. The main radical produced by mitochondria is superoxide anion and the intramitochondrial antioxidant systems should scavenge this radical to avoid oxidative damage, which leads to impaired ATP production. During aging and some neurodegenerative diseases, oxidatively damaged mitochondria are unable to maintain the energy demands of the cell leading to an increased production of free radicals. Both processes, i.e., defective ATP production and increased oxygen radicals, may induce mitochondrial-dependent apoptotic cell death. Melatonin has been reported to exert neuroprotective effects in several experimental and clinical situations involving neurotoxicity and/or excitotoxicity. Additionally, in a series of pathologies in which high production of free radicals is the primary cause of the disease, melatonin is also protective. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress. The discoveries of new actions of melatonin in mitochondria support a novel mechanism, which explains some of the protective effects of the indoleamine on cell survival.

Publication Types:
· Research Support, Non-U.S. Gov't
· Review

PMID: 11270481 [PubMed - indexed for MEDLINE]


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