CO2 Levels Modify Neuronal Function and ATP [Purinergic Signalling in the Brain].

To understand our ongoing ideas please look at our post on a Potential two Step Marker for Bipolar Depressive Illness [to start] and our post on How to Save a Manic Depressive Life.

1] We have a potential new 2 step biomarker for bipolar illness. Ventilatory issues and [hidden] hypercapnia can cause specific patterns of “odd behaviour”, mood and locomotor activity.


Adv Exp Med Biol . 2020;1202:1-12. doi: 10.1007/978-3-030-30651-9_1.

Introduction to Purinergic Signalling in the Brain

Geoffrey Burnstock 1 PMID: 32034706 DOI: 10.1007/978-3-030-30651-9_1


ATP is a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the brain. There is a widespread presence of both adenosine (P1) and P2 nucleotide receptors in the brain on both neurons and glial cells. Adenosine receptors play a major role in presynaptic neuromodulation, while P2X ionotropic receptors are involved in fast synaptic transmission and synaptic plasticity. P2Y G protein-coupled receptors are largely involved in presynaptic activities, as well as mediating long-term (trophic) signalling in cell proliferation, differentiation and death during development and regeneration. Both P1 and P2 receptors participate in neuron-glial interactions. Purinergic signalling is involved in control of cerebral vascular tone and remodelling and has been implicated in learning and memory, locomotor and feeding behaviour and sleep. There is increasing interest in the involvement of purinergic signalling in the pathophysiology of the CNS, including trauma, ischaemia, epilepsy, neurodegenerative diseases, neuropsychiatric and mood disorders, and cancer, including gliomas.

Keywords: ATP; Adenosine; Cotransmission; Glia; Gliomas; Memory; Neurodegenerative diseases; Neuromodulation; Neuron-gial interactions; Purinoceptors; Sleep; Trophic signalling.

Purinergic signalling: from normal behaviour to pathological brain function

Geoffrey Burnstock 1Ute KrügelMaria P AbbracchioPeter Illes

Prog Neurobiol . 2011 Oct;95(2):229-74. doi: 10.1016/j.pneurobio.2011.08.006.Epub 2011 Sep 1. PMID: 21907261 DOI: 10.1016/j.pneurobio.2011.08.006


Purinergic neurotransmission, involving release of ATP as an efferent neurotransmitter was first proposed in 1972. Later, ATP was recognised as a cotransmitter in peripheral nerves and more recently as a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the CNS. Both ATP, together with some of its enzymatic breakdown products (ADP and adenosine) and uracil nucleotides are now recognised to act via P2X ion channels and P1 and P2Y G protein-coupled receptors, which are widely expressed in the brain. They mediate both fast signalling in neurotransmission and neuromodulation and long-term (trophic) signalling in cell proliferation, differentiation and death. Purinergic signalling is prominent in neurone-glial cell interactions. In this review we discuss first the evidence implicating purinergic signalling in normal behaviour, including learning and memory, sleep and arousal, locomotor activity and exploration, feeding behaviour and mood and motivation. Then we turn to the involvement of P1 and P2 receptors in pathological brain function; firstly in trauma, ischemia and stroke, then in neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s, as well as multiple sclerosis and amyotrophic lateral sclerosis. Finally, the role of purinergic signalling in neuropsychiatric diseases (including schizophrenia), epilepsy, migraine, cognitive impairment and neuropathic pain will be considered.

Neuron. Author manuscript; available in PMC 2007 Jul 17.Published in final edited form as:Neuron. 2005 Dec 22; 48(6): 1011–1023. doi: 10.1016/j.neuron.2005.11.009PMCID: PMC1924599NIHMSID: NIHMS23429PMID: 16364904

Adenosine and ATP Link PCO2 to Cortical Excitability via pH

Chris G. Dulla,1,4Peter Dobelis,1Tim Pearson,2Bruno G. Frenguelli,2Kevin J. Staley,1,* and  Susan A. Masino3


In addition to affecting respiration and vascular tone, deviations from normal CO2 alter pH, consciousness, and seizure propensity. Outside the brainstem, however, the mechanisms by which CO2 levels modify neuronal function are unknown. In the hippocampal slice preparation, increasing CO2, and thus decreasing pH, increased the extracellular concentration of the endogenous neuromodulator adenosine and inhibited excitatory synaptic transmission. These effects involve adenosine A1 and ATP receptors and depend on decreased extracellular pH. In contrast, decreasing CO2 levels reduced extracellular adenosine concentration and increased neuronal excitability via adenosine A1 receptors, ATP receptors, and ecto-ATPase. Based on these studies, we propose that CO2-induced changes in neuronal function arise from a pH-dependent modulation of adenosine and ATP levels. These findings demonstrate a mechanism for the bidirectional effects of CO2 on neuronal excitability in the forebrain.

So exciting!

To be continued….

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