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Nicholas DALE "New mechanisms of CO2­ and glucose sensing in the brain"

Abstract :

The brain measures and regulates important aspects of the body's internal state that are vital for life.
I will consider novel mechanisms underlying the measurement and regulation of two key aspects of the internal state: the partial pressure of CO2 (PCO2) in arterial blood and the concentration of glucose in the brain.

As the level of arterial PCO2 determines the pH of all bodily fluids, the homeostatic regulation of arterial PCO2 via adaptive changes in breathing is an important physiological function. While most attention has been focused on brainstem chemosensors that measure pH, we have discovered a novel molecular mechanism by which CO2 can be directly detected via hemichannels comprised of connexin 26 (Cx26). These hemichannels open in a CO2-sensitive manner to allow the release of ATP, which then excites the respiratory network to evoke the necessary adaptive changes in breathing. Our results introduce new principles into the field of respiratory chemosensitivity. As Cx26 is widely distributed throughout the surface of the brain, it may also contribute to further important physiological processes such as the CO2-dependent control of cerebral blood flow and CO2-dependent arousal.

In the second part of my talk I will demonstrate a novel form of ATP-mediated glucose-sensing by specialized glial-like cells called hypothalamic tanycytes. Tanycytes line the fluid filled 3rd ventricle of the brain, contact the cerebrospinal fluid and send projections into the hypothalamus, towards areas such as the arcuate nucleus and ventromedial hypothalamic nucleus that are central to the regulation of food intake and energy homeostasis. They are ideally placed as chemosensors of the cerebrospinal fluid and I will argue that tanycytes may be an overlooked contributor to the hypothalamic networks that integrate a variety of signals related to the nutritional and energy status of an individual and control the drive to feed.

These two examples of ATP-mediated signaling have conceptual similarities. In both cases ATP acts at a brain surface: external for CO2 chemosensory transduction; and internal for glucose measurement. Furthermore, ATP also acts in both cases as a mediator that transduces external environmental signals to actions within the brain itself.

Selected publications

Huckstepp, R. T. R. and Dale, N.(2011) 'CO2-dependent opening of an inwardly rectifying K+ channel' Pflugers Archiv (online) 461 (3), 337 - 344 (1432-2013)
Huckstepp, R. T. R., Eason, R., Sachdev, A. and Dale, N.(2010) 'CO2-dependent opening of connexin 26 and related β connexins' Journal Of Physiology 588 (20), 3921 - 3931 (0022-3751)
Huckstepp, R. T. R., id Bihi, R., Eason, R., Spyer, K. M., Dicke, N., Willecke, K., Marina, N., Gourine, A. V. and Dale, N.(2010) 'Connexin hemichannel-mediated CO2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity' Journal Of Physiology 588 (20), 3901 - 3920 (0022-3751)

Scientific focus :

Neurophysiological studies
Our interests presently concentrate around the investigation of chemical signalling in the brain. One common theme is purinergic signalling by ATP and adenosine and its roles in several different functional contexts such as: centrally mediated chemosensitive reflexes involved in the control of breathing and arousal; signalling by hypothalamic tanycytes in the context of the control of body weight and food intake; homeostatic control of sleep; endogenous neuroprotective mechanisms in the brain; and during early development. We use a combination of electrophysiological, imaging and biosensing methods to study these problems.

Technology development
We have an active program to provide novel analytical tools for neuroscience research. In particular we are developing microelectrode biosensors specific for a number of transmitters to enable better exploration of chemical signalling in the nervous system. We have concentrated on microelectrode biosensors for the purines and have formed the Warwick Biosensors Group to further this aim. We are also developing biosensors for other analytes (such as glutamate, lactate, D-serine, acetylcholine) and have developed a range of highly selective biosensors for clinical diagnostic purposes. This latter work is linked to a spin out company Sarissa Biomedical Ltd specifically devoted to the commercialization of our biosensors and the development of diagnostic tools.

Marc Landry