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Evolution brings Ca2+ and ATP together to control life and death
Theo Murphy scientific meeting organised by Professor Ole Petersen CBE FRS and Professor Alexej Verkhratsky.
The evolution of the major cellular signalling cascades and the link between the two most ancient signalling molecules, namely ATP and Ca2+ are the focal points of the meeting. We shall explore how the evolutionary trends shaped these signalling systems in different cell types, and how these two systems became the ultimate pathways regulating cell survival and death.
Call for posters - deadline 1 March 2016
The meeting will include a poster session and the call for abstracts is currently open. To submit a poster abstract for consideration please email the events team with the poster title, authors, affilliations and an abstract of not more than 200 words. Please note that places are limited and are selected at the scientific organisers discretion.
Attending this event
This is a residential conference, which allows for increased discussion and networking. It is free to attend, however participants need to cover their accommodation and catering costs.
Enquiries: Contact the events team
Organisers
Schedule
Chair
Professor Ole Petersen CBE FRS, Cardiff University, UK
Professor Ole Petersen CBE FRS, Cardiff University, UK
Ole Petersen is MRC Professor at Cardiff University's School of Biosciences. He pioneered patch clamp single channel and whole cell current recording in epithelial cells, characterizing the ion channels that control fluid secretion. He discovered hormone-evoked local calcium signal control of exocrine secretion. Petersen discovered how alcohol and products of alcohol and fatty acids evoke excessive calcium release from intracellular stores in the pancreas thereby initiating pancreatitis, an often fatal human disease in which the pancreas digests itself. He has defined the intracellular mechanisms and shown how they can be blocked. Petersen was elected Fellow of The Royal Society in 2000 and Member of the German National Academy of Sciences Leopoldina in 2010. He received the Czech Academy of Sciences’ Purkynĕ Medal in 2003 and became Commander of the Order of the British Empire in 2008. Petersen chaired the Biological Sciences Panel in the UK Government's 2014 Research Excellence Framework (REF2014).
| 09:05 - 09:30 |
Evolution of Ca2+ signalling
"Is evolution a theory, a system, or a hypothesis? It is much more - it is a general postulate to which all theories, all hypotheses, all systems must henceforward bow and which they must satisfy in order to be thinkable and true. Evolution is a light which illuminates all facts, a trajectory which all lines of thought must follow-this is what evolution is." Pierre Teilhard de Chardin, quoted from Theodosius Dobzhansky, Nothing in Biology Makes Sense Except in the Light of Evolution, The American Biology Teacher, Vol. 35, No. 3 (Mar., 1973), pp. 125-129 All living cells maintain exceptionally low concentration of free Ca2+ ions in their cytosol; this is a universal attribute of life in the Earth. Extremely steep trans-plasmalemmal gradient for Ca2+ sets the background for utilisation of Ca2+ ions as iniquitous and pluripotent signalling molecules that regulate numerous cellular processes. To create and maintain low cytosolic Ca2+ concentration numerous transporting molecules are required and it is hard to conceive that the very first cells were in possession of these molecules from their very emergence which happened ~3.5 billion years ago. Eukaryotes have inherited pumps and antiporters and expanded their deployment from plasma membrane to intracellular organelles; similarly Ca2+-binding proteins become available to some of these intracellular compartments. This allowed highly localised control over Ca2+ in cells of continuously increasing size and complexity. This is particularly true of compartments involved in trafficking (for example the endoplasmic reticulum) function of which is largely governed by calcium. Probably evolution of complex cell structure was going in parallel with the evolution of Ca2+ signalling. In eukaryotes, Ca2+ has, thus, become a dominant regulator of intracellular vesicle traffic. This had to be “invented”, not only for influx under widely different regulation principles – modification by extracellular and intracellular signals – but also for mobilization of Ca2+ from intracellular stores and vesicles undergoing trafficking. Beyond the endoplasmic reticulum, these include exo- and endocytotic as well as recycling and lysosomal vesicles. At the end of this long lasting evolutionary journey the sophisticated and coordinated Ca2+ signalling system became omnipresent. Besides Ca2+ pumps and transporters this system includes Ca2+ channels responsible for fast and topologically defined Ca2+ diffusion across plasma membrane and endomembranes. 
Professor Alexej Verkhratsky, University of Manchester, UK
Professor Alexej Verkhratsky, University of Manchester, UKProfessor Alexei Verkhratsky, MD, PhD, D.Sc., Member of Academia Europaea, Member of the German National Academy of Sciences Leopoldina, Member of Real Academia Nacional de Farmacia of Spain, was born in 1961 in Stanislaw, Galicia, Western Ukraine. Currently Alexei is Professor of Neurophysiology in the faculty of Life Sciences at the Mniversity of Manchester. In 2007 to 2010 he was a visitor professor/Head of Department of Cellular and Molecular Neurophysiology at the Institute of Experimental Medicine in Prague; he also serves as a Research Professor of the Basque Research Council, Bilbao and Adjunct Scientific Director of the Achucarro Basque Center for Neuroscience; from 2011 he is as a Honorary Visitor Professor at Kyushu University, Fukuoka, Japan. Alexei is the editor-in-chief of Cell Calcium, Receiving Editor of Cell Death & Disease and member of editorial boards of many journals. Alexei Verkhratsky is an internationally recognised scholar in the field of cellular neurophysiology. His research is concentrated on the mechanisms of inter- and intracellular signalling in the CNS, being especially focused on two main types of neural cells, on neurones and neuroglia. In recent years he studies the glial pathology in Alzheimer disease. He authored a pioneering hypothesis of astroglial atrophy as a mechanism of neurodegeneration. Scientometry: Prof Verkhratsky authored and edited 12 books and published ~ 350 papers and chapters. His papers were cited >12000 times, H-index 64 (ISI, 04/2015). |
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| 09:45 - 10:15 |
Mitochondrial ATP production
Professor Sir John Walker FMedSci FRS, MRC-Mitochondrial Biology Unit, UK
Professor Sir John Walker FMedSci FRS, MRC-Mitochondrial Biology Unit, UKProfessor Sir John Walker FRS studied chemistry at St Catherine’s College Oxford. After periods of study and research at the University of Wisconsin USA, and The Pasteur Institute in Paris, in 1974 he joined the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, where he established the details of the modified genetic code of mitochondria, helped to discover overlapping genes in bacteriophages and discovered the two eponymous protein sequence motifs involved in binding nucleotides. They are the most widely dispersed motifs in the entire biological kingdom. Here, he also developed his interest in how energy in food is converted into the molecule ATP, the energy currency of life. In 1994, his work led to the realisation that in a complex molecular machine in our bodies, the energy released by the oxidation of dietary sugars and fats is coupled by a mechanical rotary mechanism to the chemical synthesis of ATP. This work led to the award of the Nobel Prize in Chemistry in 1997. In 1998, he was appointed Director of the MRC Dunn Human Nutrition Unit in Cambridge, which became the MRC Mitochondrial Biology Unit in 2008. Since 2013 he has been Director Emeritus. Here he continues to delve deeper into the fundamental basis of energy conversion in biology. He is a Fellow of the Royal Society, and in 2012, he received its Copley Medal, the UK’s highest scientific accolade. He is also a Fellow of the Academy of Medical Sciences, a Fellow of Sidney Sussex College, Cambridge, a Foreign Member of L’Accademia Nazionale dei Lincei, the Royal Netherlands Academy of Arts and Sciences, The Royal Society of New Zealand and a Foreign Associate of the US National Academy of Sciences.
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| 11:00 - 11:30 |
Ca2+ and cAMP signalling in mitochondria
Professor Tullio Pozzan, University of Padua, Italy
Professor Tullio Pozzan, University of Padua, ItalyProfessor Tullio Pozzan is a Professor of General Pathology. He is a member of the European Molecular Biology Organization (EMBO) (1994), the Academia Galileiana (1997), the Academia Europaea (1998), the Accademia dei Lincei (2001), the National Academy of Sciences of the USA (2006) and is a Fellow of the Royal Society of Canada (2013). Professor Pozzan has been President of the European Cell Biology Organisation (ECBO) (1999-2001), President of the Gordon Conference on Ca2+ signalling (2001) and President of the Italian Society of Cell Biology (1999 – 2004). He has received the Feltrinelli Prize for Medicine (2000) and received Laurea ad Honorem, University of Geneva (Switzerland) (2011).He has acted as Scientific Director of the Venetian Institute of Molecular Medicine (VIMM) (2005-2014) and Director of the Institute of Neuroscience of the National Research Council of Italy (CNR) (2009 – 2013). He is currently Director of the CNR Department of Biomedical Sciences. |
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| 11:45 - 12:15 |
Short and long-term (trophic) purinergic signalling
There is long-term (trophic) purinergic signalling involving cell proliferation, differentiation, motility and death in the development and regeneration of most systems of the body, in addition to fast purinergic signalling in neurotransmission, neuromodulation and secretion. Examples of short-term purinergic signalling during sympathetic, parasympathetic and enteric neuromuscular transmission and in synaptic transmission in ganglia and in the central nervous system are described, as well as in neuromodulation and secretion. Long-term trophic signalling is described in the immune/defence system, stratified epithelia in visceral organs and skin, embryological development, bone formation and resorption and in cancer. It is likely that the increase in intracellular Ca2+ in response to purinoceptor activation participates in many short- and long-term physiological effects. 
Professor Geoffrey Burnstock FRS, University College London, UK
Professor Geoffrey Burnstock FRS, University College London, UKProfessor Geoffrey Burnstock completed his PhD at King's College and University College London. He was head of the Department of Zoology, Melbourne University (1964-1975) before moving to London to head the Department of Anatomy and Developmental Biology, UCL until 1997. He is currently President of the Autonomic Neuroscience Centre, University College Medical School, UK. He is a Fellow of the Australian Academy of Sciences (1971), Royal Society (1986) and Academy of Medical Sciences (1998). He was awarded the Royal Society Gold Medal (2000) and has over 1510 publications and an h-index of 134. |
Chair
Professor Sir John Walker FMedSci FRS, MRC-Mitochondrial Biology Unit, UK
Professor Sir John Walker FMedSci FRS, MRC-Mitochondrial Biology Unit, UK
Professor Sir John Walker FRS studied chemistry at St Catherine’s College Oxford. After periods of study and research at the University of Wisconsin USA, and The Pasteur Institute in Paris, in 1974 he joined the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, where he established the details of the modified genetic code of mitochondria, helped to discover overlapping genes in bacteriophages and discovered the two eponymous protein sequence motifs involved in binding nucleotides. They are the most widely dispersed motifs in the entire biological kingdom. Here, he also developed his interest in how energy in food is converted into the molecule ATP, the energy currency of life. In 1994, his work led to the realisation that in a complex molecular machine in our bodies, the energy released by the oxidation of dietary sugars and fats is coupled by a mechanical rotary mechanism to the chemical synthesis of ATP. This work led to the award of the Nobel Prize in Chemistry in 1997. In 1998, he was appointed Director of the MRC Dunn Human Nutrition Unit in Cambridge, which became the MRC Mitochondrial Biology Unit in 2008. Since 2013 he has been Director Emeritus. Here he continues to delve deeper into the fundamental basis of energy conversion in biology. He is a Fellow of the Royal Society, and in 2012, he received its Copley Medal, the UK’s highest scientific accolade. He is also a Fellow of the Academy of Medical Sciences, a Fellow of Sidney Sussex College, Cambridge, a Foreign Member of L’Accademia Nazionale dei Lincei, the Royal Netherlands Academy of Arts and Sciences, The Royal Society of New Zealand and a Foreign Associate of the US National Academy of Sciences.
| 13:15 - 13:45 |
Store-operated CRAC channels and upper airway disease
Ca2+ release-activated Ca2+ (CRAC) channels are a major route for Ca2+ entry in eukaryotic cells. The channels are activated by the emptying of intracellular Ca2+ stores, which is sensed by the ER Ca2+ sensors STIM1 and STIM2. STIM proteins then bind directly to Orai proteins in the plasma membrane, which comprise the pore-forming subunit of the CRAC channel. Ca2+ influx through CRAC channels activates a plethora of key functional responses including exocytosis, metabolism, cell movement and regulated gene expression. We have shown in mast cells that spatially restricted Ca2+ signals, called Ca2+ microdomains, near open CRAC channels activate a biochemical pathway that leads to secretion of the pro-inflammatory molecule leukotriene C4 (LTC4). Interestingly, LTC4 activates cysteinyl leukotriene type I receptors on mast cells, which lead to opening of CRAC channels. This develops into a positive feedback cycle that sustains mast cell activation and results in the propagation of an intercellular Ca2+ wave through the mast cell population. Inhibition of CRAC channels is an effective way to damp down these Ca2+ waves. The relevance of targeting this feed forward loop to upper airway diseases, such as nasal polyposis, will be discussed. 
Professor Anant Parekh, University of Oxford, UK
Professor Anant Parekh, University of Oxford, UKAnant Parekh was a medical student at Oxford University, where he obtained his undergraduate and doctoral degrees (both at University College). He then moved, initially as an Alexander Von Humboldt Scholar, to the Max Planck Institute for biophysical Chemistry in Goettingen, Germany, where he worked in Professor Erwin Neher’s department with Professor Walter Stuehmer and then Professor Reinhold Penner. He moved back to Oxford (Physiology) in 1997 as a Wellcome Trust Career Development Fellow and Sir Edward Abraham Research Fellow at Keble College. He was subsequently awarded a Lister Institute Senior Research Fellowship, Amersham Medical Fellowship (Keble College) and then Monsanto Senior Research Fellowship (Exeter College, Oxford). In 2002, he was appointed to a proleptic University Lectureship (Physiology Department) and Tutorial Fellowship (Lady Margaret Hall). In the same year, he was awarded a personal chair. |
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| 14:00 - 14:30 |
Calcium and ATP control of cellular pathology: Pancreatitis
In pancreatic acinar cells, acetylcholine and cholecystokinin evoke repetitive local cytosolic Ca2+ spikes in the secretory region. This causes uptake of Ca2+ into the mitochondria generating ATP and triggering the physiological secretion of digestive pro-enzymes. The human disease acute pancreatitis, due to excessive alcohol intake, gallstone complications or side effects of L-asparaginase treatment of acute lymphoblastic leukaemia, is in all cases triggered by excessive and sustained elevations of the global cytosolic Ca2+ concentration. This cellular Ca2+ overloading depends on Ca2+ entry via conventional CRAC (Ca2+ Release-Activated Ca2+) channels and causes intracellular protease activation and auto-digestion. Due to opening of the mitochondrial permeability transition pore, ATP levels are severely reduced and the overall result is necrosis followed by inflammation. One of the activated proteases leaking out of the necrotic acinar cells is kallikrein, which can liberate bradykinin from plasma kininogen. The elevated plasma bradykinin level elicits Ca2+ signals in peri-acinar stellate cells. The initial Ca2+ rise is due to intracellular Ca2+ release, but is quickly followed by a plateau phase depending on Ca2+ entry via CRAC channels. In case of repeated attacks of acute pancreatitis, which can then become chronic, the stellate cells produce a fibrotic (and potentially cancer promoting) extracellular matrix. Blockade of CRAC channels prevents all the adverse effects in both acinar and stellate cells and is currently the most promising rational therapy for pancreatitis.
Professor Ole Petersen CBE FRS, Cardiff University, UK
Professor Ole Petersen CBE FRS, Cardiff University, UKOle Petersen is MRC Professor at Cardiff University's School of Biosciences. He pioneered patch clamp single channel and whole cell current recording in epithelial cells, characterizing the ion channels that control fluid secretion. He discovered hormone-evoked local calcium signal control of exocrine secretion. Petersen discovered how alcohol and products of alcohol and fatty acids evoke excessive calcium release from intracellular stores in the pancreas thereby initiating pancreatitis, an often fatal human disease in which the pancreas digests itself. He has defined the intracellular mechanisms and shown how they can be blocked. Petersen was elected Fellow of The Royal Society in 2000 and Member of the German National Academy of Sciences Leopoldina in 2010. He received the Czech Academy of Sciences’ Purkynĕ Medal in 2003 and became Commander of the Order of the British Empire in 2008. Petersen chaired the Biological Sciences Panel in the UK Government's 2014 Research Excellence Framework (REF2014). |
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| 15:15 - 15:45 |
The roles of Ca2+ and ATP in pancreatitis
Acute pancreatitis (AP) is a leading cause of hospitalization among non-malignant gastrointestinal disorders. The mortality of severe AP can reach 30-50%, which is most probably due to the lack of specific treatment. Therefore AP is a major healthcare problem, which urges researchers to identify novel drug targets. Studies from the last decades highlighted that the toxic cellular Ca2+ overload and mitochondrial damage are key pathogenic steps in the disease development affecting both acinar and ductal cell functions. Moreover recent observations showed that modifying the cellular Ca2+ signaling might be beneficial in AP. The inhibition of Ca2+ release from the endoplasmic reticulum, or the activity of plasma membrane Ca2+ influx channels decreased the severity of AP in experimental models. Similarly, inhibition of mitochondrial permeability transition pore opening also seems to improve the outcome of AP in in vivo animal models. Unfortunately, only small amount of MPTP blockers are under detailed clinical investigation. Unsuccessful outcome in both MITOCARE and CIRCUS trials suggests that more pharmacological development is crucially needed to test whether interventions in MTMT openings and/or Ca2+ homeostasis of the cells can be specific targets in prevention or treatment of cell damage. 
Professor Peter Hegyi, University of Szeged, Hungary
Professor Peter Hegyi, University of Szeged, HungaryPeter Hegyi is a gastroenterologist, head of the Translational Pancreatic Research Centre at the University of Szeged. He spent around 4 years at different UK's Physiology Departments (University of Newcastle and Liverpool) between 2000-2008 as a posdtoctoral research fellow. He could successfully integrate the top quality basic knowledge learned in the UK into his clinical experience. He is currently looking for biological targets and mechanisms susceptible to pharmacological intervention in his focus on prophylactics and specific treatments for pancreatitis within the framework of the Hungarian Academy of Sciences' Programme for Excellence (Momentum). He had pivotal role of discovering the role of pancreatic ductal cells during pancreattis. It is important to mention that some of these research were supported by the Royal Society and the Wellcome Trust. Peter Hegyi is involved in scientific education very much. Eleven Ph.D. students have been graduated in his lab between 2008-2015 and most of them followed their research activity in the UK. |
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| 16:00 - 16:30 |
ATP-sensitive K+channels and diabetes
Professor Frances Ashcroft FRS, University of Oxford, UK
Professor Frances Ashcroft FRS, University of Oxford, UKFrances Ashcroft is Professor of Physiology at the University of Oxford, a Fellow of Trinity College, Oxford and a Fellow of the Royal Society of London. Her research aims to elucidate how changes in blood glucose levels regulate insulin secretion from the pancreas and how this process is impaired in diabetes. She discovered that the ATP-sensitive potassium (KATP) channel serves as the molecular link between glucose elevation and insulin secretion. Mutations in KATP channel genes cause a rare inherited form of diabetes (neonatal diabetes), and her work has helped enable patients with this disorder to switch from insulin injections to drug therapy. She has written two books for the general reader: Life at the Extremes and The Spark of Life. |
Chair
Professor Alexej Verkhratsky, University of Manchester, UK
Professor Alexej Verkhratsky, University of Manchester, UK
Professor Alexei Verkhratsky, MD, PhD, D.Sc., Member of Academia Europaea, Member of the German National Academy of Sciences Leopoldina, Member of Real Academia Nacional de Farmacia of Spain, was born in 1961 in Stanislaw, Galicia, Western Ukraine. Currently Alexei is Professor of Neurophysiology in the faculty of Life Sciences at the Mniversity of Manchester. In 2007 to 2010 he was a visitor professor/Head of Department of Cellular and Molecular Neurophysiology at the Institute of Experimental Medicine in Prague; he also serves as a Research Professor of the Basque Research Council, Bilbao and Adjunct Scientific Director of the Achucarro Basque Center for Neuroscience; from 2011 he is as a Honorary Visitor Professor at Kyushu University, Fukuoka, Japan. Alexei is the editor-in-chief of Cell Calcium, Receiving Editor of Cell Death & Disease and member of editorial boards of many journals.
Alexei Verkhratsky is an internationally recognised scholar in the field of cellular neurophysiology. His research is concentrated on the mechanisms of inter- and intracellular signalling in the CNS, being especially focused on two main types of neural cells, on neurones and neuroglia. In recent years he studies the glial pathology in Alzheimer disease. He authored a pioneering hypothesis of astroglial atrophy as a mechanism of neurodegeneration.
Scientometry:
Prof Verkhratsky authored and edited 12 books and published ~ 350 papers and chapters. His papers were cited >12000 times, H-index 64 (ISI, 04/2015).
| 09:00 - 09:30 |
P2X receptors
P2X and P2Y receptors were distinguished by Burnstock & Kennedy (1985) on the basis of differential actions of ATP analogs, notably ab-methylene-ATP and 2-methythio-ATP. P2Y receptors were involved in relaxation of intestinal smooth muscle, whereas P2X receptors were responsible for contraction of smooth muscle of the bladder and vas deferens. The eight P2Y receptors (numbered 1, 2, 4, 6, 11, 12, 13 and 14) are class A G-protein coupled receptors activated by ATP, ADP or UTP. P2X receptors are trimeric membrane proteins that form cation channels activated by ATP. The seven P2X receptor genes in mammals encode proteins with intracellular N- and C-termini, and two membrane spanning domains separated by a large extracellular domain: channels form as homomers (numbered 1, 2, 3, 4, 5, 7) or heteromers (2/3, 1/5). In overall topology and subunit assembly, P2X receptors resemble acid-sensing ion channels (ASIC) and epithelial sodium channels (ENaC)(Browne et al. 2010; Baconguis et al 2013). The structures of the closed and open zebrafish P2X4 receptor (at 2.9 A: Hattori & Gouaux, 2012) are completely consistent with previous studies based on functional expression and site-directed mutagenesis (Browne et al 2010). They are also supported by more recent work using disulfide locking (Stelmashenko et al. 2014), gating by lipohilic attachment (Rothwell et al 2014) and gating by light using an attached bis(maleimido)azobenzene (Browne et al 2014). 
Emeritus Professor Alan North FRS, University of Manchester, UK
Emeritus Professor Alan North FRS, University of Manchester, UK(Richard) Alan North graduated in physiology (BSc 1969), medicine (MB ChB 1969) and pharmacology (PhD 1973) from the University of Aberdeen. After briefly working as a physician, Professor North held appointments as Associate Professor of Pharmacology at Loyola University Stritch School of Medicine in Chicago, Professor of Neuropharmacology at the Massachusetts Institute of Technology, Senior Scientist and Professor of Neurology at the Vollum Institute of Oregon Health Sciences University, Principal Scientist at the Geneva Biomedical Research Institute (a division of GlaxoWellcome Research and Development in Switzerland), and Professor of Molecular Physiology at the University of Sheffield. He joined the University of Manchester as Vice-President in 2004, serving as Dean of its Faculty of Life Sciences (2004 to 2008), Dean of its Faculty of Medical and Human Sciences (2006-2011) and he was the founding Director of the Manchester Academic Health Science Centre (2008-2010). From late 2013, he has been Emeritus Professor at the University of Manchester. His research contributions have been in the understanding of the ionic mechanisms involved in the actions of neurotransmitters and drugs (particularly opiates), and in the molecular physiology of extracellular of adenosine triphosphate acting at P2X receptors. He was Editor-in-Chief of the British Journal of Pharmacology as well as serving two terms as an editor of The Journal of Physiology. He was President of The Physiological Society from 2001-2004. He served on the Medical Research Council, and chaired several of its review committees. Alan is a Fellow of the Royal Society, the Royal College of Physicians, the Academy of Medical Sciences, and Academia Europae, and holds Honorary Membership of The Physiological Society and the British Pharmacological Society. |
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| 09:45 - 10:15 |
The glymphatic system
We have recently described a macroscopic pathway in the central nervous system – the glymphatic system that facilitates the clearance of interstitial waste products from neuronal metabolism. Glymphatic clearance of macromolecules is driven by cerebrospinal fluid (CSF) that flows in along para-arterial spaces and through the brain parenchyma via support from astroglial aquaporin-4 water channels. The glymphatic circulation constitutes a complete anatomical pathway; para-arterial CSF exchanges with the interstitial fluid, solutes collect along para-venous spaces, then drain into the vessels of the lymphatic system for ultimate excretion from the kidney or degradation in the liver. As such, the glymphatic system represents a novel and unexplored target for prevention and treatment of neurodegenerative diseases. 
Professor Maiken Nedergaard, Københavns University, Denmark
Professor Maiken Nedergaard, Københavns University, DenmarkDr Nedergaard is Professor of Neurosurgery and Co-Director of the Center for Translational Neuromedicine at the University of Rochester Medical Center (URMC) in Rochester, NY. She is also Professor of Glial Cell Biology and Co-Director of the Center for Translational Neuroscience at the University of Copenhagen, Denmark. Her multiple interests range from basic research on neuron-glia interactions to their role in aging, small vessel disease, seizure disorders and cerebral blood flow. Forefront amongst her discovery is the identification of the glymphatic system, a brain equivalent of the lymphatic system within which cerebrospinal fluid diffuses rapidly and mixes with interstitial fluids, thereby filtering metabolic byproducts that accumulate due to neuronal activity. Most recently, she published a landmark study in Science showing that the glymphatic system dramatically expands during sleep compared to waking – brain cleaning and detoxification is thus greatly facilitated during sleep, providing a novel and direct explanation for what we all generally consider sleep’s restorative effect. |
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| 11:00 - 11:30 |
Calcium-dependent memory traces in neurons and glia
The accumulation of amyloid-beta in the brain is an essential feature of Alzheimer’s disease (AD). However, the impact of amyloid-beta-accumulation on the dysfunction of neurons and circuits in vivo is still poorly understood. The neurodegeneration observed in AD has been initially associated with a progressive decrease in neuronal activity. Instead, in a mouse model of amyloidosis, we demonstrated that a substantial fraction of cortical neurons exhibit a massive increase in neuronal activity. These “hyperactive” neurons were located predominantly near the plaques of amyloid beta (Abeta)-depositing mice. In the visual cortex of the same mouse model, we found a progressive deterioration of sensory integration that paralleled the age-dependent increase of the amyloid-beta load. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons before the formation of plaques, suggesting that soluble species of Abeta may underlie the impaired neuronal activity. In support of this model, we found that the acute treatment of transgenic mice with a gamma-secretase inhibitor reduced soluble Abeta levels and rescued the neuronal dysfunction. Recently, we discovered an Abeta-dependent impairment of slow-wave propagation, which causes a breakdown of the characteristic long-range coherence of slow-wave activity in the mammalian brain. We demonstrated that this impairment can be rescued by enhancing GABAAergic inhibition and, thereby, reducing the level of hyperactivity. Together, our results support the notion that neuronal hyperactivity is a major cellular mechanism underlying circuit dysfunction in AD. 
Professor Arthur Konnerth, Technische Universitaet Muenchen, Germany
Professor Arthur Konnerth, Technische Universitaet Muenchen, GermanyArthur Konnerth is currently the Friedrich-Schiedel-Chair of Neuroscience and Director of the Institute for Neuroscience at the Technical University Munich. He is a member of the German National Academy of Sciences Leopoldina, the Academia Europaea and the Bavarian Academy of Sciences. His current research is focused on the development and application of methods that allow a quantitative understanding of function and dysfunction of neurons and circuits in the intact brain. A major goal is a better understanding of the cellular and circuit mechanisms of learning and memory in the healthy brain, as well as the pathophysiology underlying the impairment of cognition and memory in Alzheimer’s disease. |
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| 11:45 - 12:15 |
Regulation of neuronal calcium channel trafficking, subcellular localisation and function by auxiliary subunits
Voltage-gated calcium channels are essential for the function of all excitable cells, since they link changes in excitation to entry of Ca2+ into the cells. The effects of Ca2+ in neurons include neurotransmitter release, and changes in gene expression. The CaV2 family of calcium channels mediate neurotransmitter release and are strongly expressed in presynaptic terminals. I will address the interplay between the function of neuronal calcium channels and the role of their auxiliary subunits, particularly α2δ, in excitable cells, and describe what happens when the channels undergo aberrant trafficking. There is increasing evidence that voltage-gated calcium channel dysfunction is involved in a number of disorders, including the development of chronic pain, a major source of morbidity in the population. In experimental models of chronic neuropathic pain, in which the peripheral axons of sensory dorsal root ganglion neurons are damaged, the auxiliary α2δ-1 subunit is upregulated strongly in the damaged neurons. In my presentation, I will discuss the role of the auxiliary α2δ subunits in calcium channel trafficking and function, in both cell lines and in neurons from wild-type and α2δ-1 knockout mice. I will also relate this to changes in channel distribution that occur in neuropathic pain. 
Professor Annette C Dolphin FRS, University College London, UK
Professor Annette C Dolphin FRS, University College London, UKProfessor Annette C. Dolphin received her BA in Natural Sciences (Biochemistry) from the University of Oxford and her PhD at the Institute of Psychiatry in London. She held postdoctoral fellowships at the College de France in Paris, and at Yale University, before returning to a post at the National Institute for Medical Research. She then took up a lectureship at St. George's Hospital Medical School, London, and was appointed to the chair of Pharmacology at the Royal Free Hospital School of Medicine, London, in 1990. Following the merger of this Department with the UCL Department in 1997, she moved to the UCL campus. She was elected to the Academy of Medical Sciences in 1999. She has received several prizes including the Sandoz Prize of the British Pharmacological Society (1986), Pfizer Prize in Biology (1991) and the G.L.Brown Prize of the Physiological Society (1994). 1st Julius Axelrod Distinguished Lecturer in Neuroscience, Toronto (2000), Gary Price memorial lecturer of British Pharmacological Society (2011). She is currently an Editor of Pharmacological Reviews. |
Chair
Emeritus Professor Alan North FRS, University of Manchester, UK
Emeritus Professor Alan North FRS, University of Manchester, UK
(Richard) Alan North graduated in physiology (BSc 1969), medicine (MB ChB 1969) and pharmacology (PhD 1973) from the University of Aberdeen. After briefly working as a physician, Professor North held appointments as Associate Professor of Pharmacology at Loyola University Stritch School of Medicine in Chicago, Professor of Neuropharmacology at the Massachusetts Institute of Technology, Senior Scientist and Professor of Neurology at the Vollum Institute of Oregon Health Sciences University, Principal Scientist at the Geneva Biomedical Research Institute (a division of GlaxoWellcome Research and Development in Switzerland), and Professor of Molecular Physiology at the University of Sheffield.
He joined the University of Manchester as Vice-President in 2004, serving as Dean of its Faculty of Life Sciences (2004 to 2008), Dean of its Faculty of Medical and Human Sciences (2006-2011) and he was the founding Director of the Manchester Academic Health Science Centre (2008-2010). From late 2013, he has been Emeritus Professor at the University of Manchester.
His research contributions have been in the understanding of the ionic mechanisms involved in the actions of neurotransmitters and drugs (particularly opiates), and in the molecular physiology of extracellular of adenosine triphosphate acting at P2X receptors. He was Editor-in-Chief of the British Journal of Pharmacology as well as serving two terms as an editor of The Journal of Physiology. He was President of The Physiological Society from 2001-2004. He served on the Medical Research Council, and chaired several of its review committees. Alan is a Fellow of the Royal Society, the Royal College of Physicians, the Academy of Medical Sciences, and Academia Europae, and holds Honorary Membership of The Physiological Society and the British Pharmacological Society.
| 13:15 - 13:45 |
ASICS regulate spontaneous inhibitory activity in hippocampus: possible implications for epilepsy
Numerous data indicate that acid-sensing ion channels (ASICs) play an important role in numerous functions in central and peripheral nervous systems ranging from memory and emotions to pain. These data correspond to a recent notion that each neuron and many glial cells of mammalian brain express at least one member of the ASICs family. However, the mechanism underlying the involvement of ASICs into neuronal activity are poorly understood or just unknown. Two exceptions, namely straightforward role of ASICs in proton-based synaptic transmission in certain limited brain areas and the role of Ca++-permeable ASIC1a subtype in ischemic cell death do not account for the plethora of ASICs-related phenomena. Using novel orthosteric ASICs blocker, we have found that ASICs specifically control the frequency of spontaneous inhibitory synaptic activity in hippocampus. Inhibition of ASICs leads to a strong increase in the frequency of spontaneous IPSCs. This effect is presynaptic since it is fully reproducible in single synaptic boutons attached to isolated hippocampal neurons. In qualitative concert with this observation, inhibition of ASIC current diminishes epileptic discharges in low Mg++ model of epilepsy in hippocampal slices and significantly reduces kainate-induced discharges in hippocampus in vivo. Our results reveal a novel significant role of ASICs. 
Professor Oleg Krishtal, Bogomoletz Institute of Physiology, Ukraine
Professor Oleg Krishtal, Bogomoletz Institute of Physiology, UkraineOleg Krishtal, Ph. D. (1971), D. Sc. (1978), born on July 5, 1945. He received his University degree in Molecular Physics from Kiev State University (1968). Since then he works all the time in Bogomoletz Institute of Physiology starting as post-graduate student and becoming its director in 2011. All his life Krishtal works in the field of neuroscience. Among the highlights of his discoveries and achievements are: first intracellular perfusion of nerve cell body (1975), proton-activated membrane conductance (1981) and ionotropic purinoreceptors in the nerve cell membrane (1983). Krishtal is Member of Academia Europaea (1990). Krishtal is the President of Ukrainian National Societies for Neuroscience and Physiology. From 1995 to 2005 O. Krishtal has been Howard Hughes Medical Institute Foreign Investigator. He is the Member of Dana Alliance. He supervised more than 20 PhDs that are working now in the leading scientific centers throughout the globe. |
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| 14:00 - 14:30 |
Deregulation of ion homeostasis and ATP support in neurodegeneration
Professor Pierluigi Nicotera, German Centre for Neurodegenerative Diseases, Germany
Professor Pierluigi Nicotera, German Centre for Neurodegenerative Diseases, GermanyProfessor Pierluigi Nicotera, a renowned scientist and leading international expert in the field of neuronal cell death, was appointed Scientific Director of DZNE in April 2009. Professor Nicotera was trained in General Medicine and Cardiology at the University of Pavia, Italy. He obtained his PhD at the Karolinska Institute in Stockholm, where he worked subsequently as associate professor. From 1995 to 2000 Nicotera headed the division of Molecular Toxicology at the University of Konstanz and was then appointed Director of the UK Medical Research Council Toxicology Unit. His research has been centred on the molecular mechanisms that lead to neuronal demise following chronic and acute insults. Loss of neuronal synaptic connections and apoptosis play central roles in neurodegenerative diseases. |
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| 15:15 - 15:45 |
Nucleotides, Ca2+ and the fate of neural stem cells
In the central nervous system (CNS), during both brain and spinal cord development, purinergic and pyrimidinergic signalling molecules (ATP, UTP and adenosine) act synergistically with peptidic growth factors in regulating the synchronized proliferation and final specification of multi-potent neural stem cells (NSCs) to neurons, astrocytes or oligodendrocytes, the myelin forming cells. Some NSCs still persist throughout adulthood in both specific "neurogenic" areas and in brain and spinal cord parenchyma, retaining the potentiality to generate all the three main types of adult CNS cells. Once CNS anatomical structures are defined, purinergic molecules participate in calcium-dependent neuron-to-glia communication and also control the behaviour of adult NSCs. After development, some purinergic mechanisms are silenced, but can be resumed after injury, suggesting a role for purinergic signaling in regeneration and self-repair also via the reactivation of adult NSCs (Ulrich et al., 2012). In this respect, at least three different types of adult NSCs participate to the response of the adult brain and spinal cord to insults: (i) stem-like cells residing in classical neurogenic niches, in particular in the ventricular-subventricular zone (VSVZ), (ii) parenchymal oligodendrocyte precursor cells (OPCs, also known as NG2-glia), and, (iii) parenchymal injury-activated astrocytes (reactive astrocytes). Here, we shall revise and discuss the purinergic regulation of these three main adult NSCs, with particular focus on how and to what extent modulation of intracellular calcium levels by purinoceptors is mandatory to determine their survival, proliferation and final fate. 
Professor Maria Abbrachio, University of Milan, Italy
Professor Maria Abbrachio, University of Milan, ItalyMaria P. Abbracchio was born and studied in Milan. She obtained her Master degree in Pharmacy in 1979, her specialization degree in Toxicology from the University of Milan in 1984, and her PhD degree in Experimental Medicine in Rome in 1988. She has been working as a scientist for about 30 years at research Institutions like the University of Milan, the University of Texas at Houston (postdoctoral fellow in 1980-81) and the University College London, UK (Honorary Research Fellow from 1992 to 1993). She is currently full professor of Pharmacology and responsible scientist of a group of 12 researchers at the University of Milan. She has been encharged of various Institutional research duties at her local University and in 2014 she has been nominated by the Rector President of the Research Observatory of the University of Milan. |
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| 16:00 - 16:30 |
Calcium, memory and Alzheimer's disease
Vitamin D is a hormone that is necessary to maintain healthy cells. It functions by regulating the low resting levels of cell signalling pathways such as those regulated by Ca2+ and reactive oxygen species (ROS). Its role in maintaining phenotypic stability of these signalling pathways depends on the ability of Vitamin D to control the expression of those components that act to reduce the levels of both Ca2+ and ROS. This regulatory role of Vitamin D is supported by both Klotho and Nrf2. A decline in the Vitamin D/Klotho/Nrf2 regulatory network may enhance the aging process and this is well-illustrated by the age-related decline in cognition in rats that can be reversed by administering Vitamin D. A deficiency in Vitamin D has also been linked to two of the major diseases in man: heart disease and Alzheimer’s disease (AD). In cardiac cells, this deficiency alters the Ca2+ transients to activate the gene transcriptional events leading to cardiac hypertrophy and the failing heart. In the case of Alzheimer’s disease (AD), it is argued that Vitamin D deficiency results in the Ca2+ landscape that initiates amyloid formation that elevates the resting level of Ca2+ to drive the memory loss that progresses to neuronal cell death and dementia. 
Professor Michael Berridge FRS, The Babraham Institute, UK
Professor Michael Berridge FRS, The Babraham Institute, UKSir Michael Berridge is a physiologist and biochemist best known for his discovery of inositol trisphophate (IP3) and the elucidation of its role as a ‘second messenger’ in the calcium signalling pathway – a mechanism by which cells translate chemical signals received at the cell surface into physiological responses. His discovery that IP3 stimulates the release of intracellular calcium, which triggers the cell’s response, came more than 30 years after identification of the first signalling molecule in the pathway, and involved detailed study of the mechanisms controlling secretion from the salivary glands of insects. Impact: The discovery of the role of IP3 has had significant impact upon a wide range of biomedical research areas such as cell proliferation, fertilisation, neural activity, memory and learning, metabolism and muscle contraction. It has enabled researchers to study and understand the physiological processes behind a variety of medical conditions including hypertension, cardiac arrhythmia and heart failure, cancer and manic depressive illness. Sir Berridge is Emeritus Babraham Fellow at the Babraham Institute. For more information, visit: http://www.babraham.ac.uk/emeritus/berridge.html |