Thursday, 7 February 2013

Purinergic signaling and energy homoeostasis in the brain

Many illnesses including CFS are increasingly associated with mitochondrial dysfunction as a major part of their pathophysiology. The consequences of such energy dysfunction are usually considered with reference to ATP's fundamental role in basic cellular metabolism, however usually neglected but also important is ATP's parallel influence on cellular function as a signaling molecule. Purinergic signaling occurs ubiquitously in the body, although I will describe below its basic effects in the brain.

ATP – Dual roles in the nervous system
ATP is involved in most aspects of neuron and glia metabolism, most notably the maintenance of transmembrane ion gradients (e.g. Na+/k+-ATPase & Ca2+-ATPase), signal transduction (e.g. cAMP formation and kinase-mediated phosphorylation) and macromolecule synthesis and movement. At a signaling level, ATP and its derivatives also function as fast co-transmitters throughout the entire nervous system via activation of various purinergic receptors 1,2. These receptors influence processes such as vasodilation, neuroplasticity and nociception (i.e. noxious/pain signaling).

Purinergic signaling & energy homeostasis
Adenosine-5’-triphosphate (ATP) is a nucleotide which consists of three phosphate groups bound to adenosine. Chemical energy is released from ATP and other nucleoside triphosphates (e.g. GTP, CTP and UTP) by hydrolysis and resulting phosphate release. At various rates of energy usage ATP can be sequentially degraded from ATP to ADP to AMP and finally adenosine. Some of these molecules can activate specific membrane-associated purinergic receptors (i.e. P1 , P2X and P2Y receptors) while AMP can activate the intracellular AMP kinase (AMPK) pathway. Hence the relative balance of ATP and its derivative metabolites directly influences cell activity through these pathways.

In the brain, under high-energy conditions the plentiful ATP supplies generally act to facilitate neuronal function and plasticity 3,4. However periods of increased energy consumption lower ATP levels and increase those of derivatives such as AMP and adenosine. This metabolic shift leads to the activation of signaling pathways which lower energy consumption and act to restore energy homeostasis. For instance a drop in the intracellular ATP: AMP ratio activates the AMPK pathway which inhibits energy consuming processes such as translation (i.e. protein synthesis) 4. Extracellular adenosine accumulation activates the A1 receptor which inhibits neuronal activity via pre- and postsynaptic mechanisms. Notably this neuronal inhibition likely represents the fundamental neuroprotective mechanism against low ATP-induced excitotoxicity in the nervous system 5,6.

The purinergic system and energy homeostasis has been further studied with regards to sleep. During prolonged wakefulness or sleep deprivation adenosine accumulation acts upon cholinergic neurons in the basal forebrain, a wake-promoting brain region, to promote sleep 7,8. Sleep may then act to promote restoration of energy homeostasis. Indeed sleep has been observed to induce a surge in ATP levels during the initial hours 9. Finally in relation to the above, it is worth noting that caffeine's major mechanism of action in the body is by strong unselective antagonism of adenosine receptors 10, which largely accounts for its stimulant properties.

Purinergic signaling & brain fog
A common part of the CFS experience and that of other neurological illnesses is ‘brain fog’ which is characterised by difficultly thinking clearly (i.e. difficulty processing, storing and retrieving information). While there may be several mechanisms mediating the symptoms of brain fog, one major common mechanism is likely to be altered purinergic signaling due to lowered ATP levels. Certainly in CFS an increase in ventricular lactate has been reported, suggesting lowered mitochondrial metabolism (i.e. CAC and/or ETC) in the brain 11. A consequent ATP shortage, particularly upon exertion, may promote accumulation of the inhibitory ATP derivatives: AMP and adenosine, which would promote cognitive suppression. If this is the case then brain adenosine accumulation may well accompany the already reported lactate increases in CFS both of which may further correlate symptoms of brain fog.

1.         Khakh, B. S. & Burnstock, G. The double life of ATP. Scientific American 301, 84–90, 92 (2009).
2.         Abbracchio, M. P., Burnstock, G., Verkhratsky, A. & Zimmermann, H. Purinergic signalling in the nervous system: an overview. Trends in neurosciences 32, 19–29 (2009).
3.         Newman, L. A., Korol, D. L. & Gold, P. E. Lactate produced by glycogenolysis in astrocytes regulates memory processing. PloS one 6, e28427 (2011).
4.         Potter, W. B. et al. Metabolic regulation of neuronal plasticity by the energy sensor AMPK. PloS one 5, e8996 (2010).
5.         Saransaari, P. & Oja, S. S. Mechanisms of Inhibitory Amino Acid Release in the Brain Stem Under Normal and Ischemic Conditions. Neurochemical research 35, 1948–56 (2010).
6.         Deckert, J. & Gleiter, C. H. Adenosine--an endogenous neuroprotective metabolite and neuromodulator. Journal of neural transmission. Supplementum 43, 23–31 (1994).
7.         Wigren, H.-K., Rytkönen, K.-M. & Porkka-Heiskanen, T. Basal forebrain lactate release and promotion of cortical arousal during prolonged waking is attenuated in aging. The Journal of neuroscience : the official journal of the Society for Neuroscience 29, 11698–707 (2009).
8.         Porkka-Heiskanen, T. & Kalinchuk, A. V Adenosine, energy metabolism and sleep homeostasis. Sleep medicine reviews 15, 123–35 (2011).
9.         Dworak, M., McCarley, R. W., Kim, T., Kalinchuk, A. V & Basheer, R. Sleep and Brain Energy Levels: ATP Changes during Sleep. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 9007–16 (2010).
10.       Ribeiro, J. A. & Sebastião, A. M. Caffeine and adenosine. Journal of Alzheimer’s disease : JAD 20 Suppl 1, S3–15 (2010).
11.       Shungu, D. C. et al. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR in biomedicine 25, 1073–87 (2012).

1 comment:

  1. Hi, you may be aware (or not) of this study on purinergic antagonist suramin:
    and full paper:

    "We found that antipurinergic therapy (APT) corrected 16 multisystem
    abnormalities that defined the ASD-like phenotype in this model. These
    included correction of the core social deficits and sensorimotor
    coordination abnormalities, prevention of cerebellar Purkinje cell loss,
    correction of the ultrastructural synaptic dysmorphology, and correction of
    the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor
    expression, and ERK1/2 and CAMKII signal transduction abnormalities. ... "