Real-time measurement of adenosine and ATP release in the central nervous system
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ORIGINAL ARTICLE
Real-time measurement of adenosine and ATP release in the central nervous system Nicholas Dale 1 Received: 4 September 2020 / Accepted: 13 September 2020 # The Author(s) 2020
Abstract This brief review recounts how, stimulated by the work of Geoff Burnstock, I developed biosensors that allowed direct real-time measurement of ATP and adenosine during neural function. The initial impetus to create an adenosine biosensor came from trying to understand how ATP and adenosine-modulated motor pattern generation in the frog embryo spinal cord. Early biosensor measurements demonstrated slow accumulation of adenosine during motor activity. Subsequent application of these biosensors characterized real-time release of adenosine in in vitro models of brain ischaemia, and this line of work has recently led to clinical measurements of whole blood purine levels in patients undergoing carotid artery surgery or stroke. In parallel, the wish to understand the role of ATP signalling in the chemosensory regulation of breathing stimulated the development of ATP biosensors. This revealed that release of ATP from the chemosensory areas of the medulla oblongata preceded adaptive changes in breathing, triggered adaptive changes in breathing via activation of P2 receptors, and ultimately led to the discovery of connexin26 as a channel that mediates CO2-gated release of ATP from cells. Keywords Biosensor . Ischaemia . Motor pattern generation . Chemosensory . Breathing . Connexin
Introduction I vividly remember the first time I heard Geoff Burnstock give a seminar. It was in 1994, and although I had known Geoff for quite some time, I had never heard him deliver a lecture. So, when he came to Bristol to give a major talk, I went with great eagerness, but also not knowing quite what to expect. What unfolded over the course of about an hour was one of the most inspiring lectures I had ever heard. At the time I had only a dim, verging on nonexistent, grasp of purinergic signalling. Geoff, at the height of his powers, convinced me, and I suspect everyone else in the audience that the purines were pretty much the answer to every physiological problem out there. I was so inspired that I got into my lab the very next day and started dabbling with ATP and adenosine. I had been running my own independent lab for about 5 years. I was working on the neuronal mechanisms of spinal motor pattern generation in the frog embryo, trying to build Hodgkin-Huxley inspired * Nicholas Dale [email protected] 1
School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK
models of the circuit, so it was natural to apply ATP and adenosine to the spinal cord and look at the consequences for motor pattern generation. Immediately I realized that there was something very interesting: both ATP and adenosine had powerful but opposing actions, on the neural circuitry that generated the swimming motor pattern. Two years of hard work, and self-tuition in the arts of purinergic signalling, resulted in a paper that described an excitatory action
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