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Evolution brings Ca2+ and ATP together to control life and death

Scientific meeting

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Starts:

March
162016

09:00

Ends:

March
172016

17:00

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Theo Murphy scientific meeting organised by Professor Ole Petersen CBE FRS and Professor Alexej Verkhratsky.

Neurotransmitter-elicited Ca2+ concentration changes in intracellular stores and the cytoplasm

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

Event organisers

Select an organiser for more information

Schedule of talks

16 March

Session 1 09:00-12:30

Session 1

4 talks Show detail Hide detail

Chairs

Professor Ole Petersen CBE FRS, Cardiff University, UK

09:05-09:30 Evolution of Ca2+ signalling

Professor Alexej Verkhratsky, University of Manchester, UK

Abstract

"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.

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09:45-10:15 Mitochondrial ATP production

Professor Sir John Walker FMedSci FRS, MRC-Mitochondrial Biology Unit, UK

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11:00-11:30 Ca2+ and cAMP signalling in mitochondria

Professor Tullio Pozzan, University of Padua, Italy

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11:45-12:15 Short and long-term (trophic) purinergic signalling

Professor Geoffrey Burnstock FRS, University College London, UK

Abstract

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.

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12:30-13:15

Lunch

Session 2 13:15-16:45

Session 2

4 talks Show detail Hide detail

Chairs

Professor Sir John Walker FMedSci FRS, MRC-Mitochondrial Biology Unit, UK

13:15-13:45 Store-operated CRAC channels and upper airway disease

Professor Anant Parekh, University of Oxford, UK

Abstract

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.

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14:00-14:30 Calcium and ATP control of cellular pathology: Pancreatitis

Professor Ole Petersen CBE FRS, Cardiff University, UK

Abstract

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.

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15:15-15:45 The roles of Ca2+ and ATP in pancreatitis

Professor Peter Hegyi, University of Szeged, Hungary

Abstract

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.

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16:00-16:30 ATP-sensitive K+channels and diabetes

Professor Frances Ashcroft FRS, University of Oxford, UK

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Poster Session 16:45-17:15

Poster Session

17 March

Session 3 09:00-12:30

Session 3

4 talks Show detail Hide detail

Chairs

Professor Alexej Verkhratsky, University of Manchester, UK

09:00-09:30 P2X receptors

Emeritus Professor Alan North FRS, University of Manchester, UK

Abstract

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).

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09:45-10:15 The glymphatic system

Professor Maiken Nedergaard, Københavns University, Denmark

Abstract

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. 

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11:00-11:30 Calcium-dependent memory traces in neurons and glia

Professor Arthur Konnerth, Technische Universitaet Muenchen, Germany

Abstract

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.

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11:45-12:15 Regulation of neuronal calcium channel trafficking, subcellular localisation and function by auxiliary subunits

Professor Annette C Dolphin FRS, University College London, UK

Abstract

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.

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12:30-13:15

Lunch

Session 4 13:15-17:00

Session 4

4 talks Show detail Hide detail

Chairs

Emeritus Professor Alan North FRS, University of Manchester, UK

13:15-13:45 ASICS regulate spontaneous inhibitory activity in hippocampus: possible implications for epilepsy

Professor Oleg Krishtal, Bogomoletz Institute of Physiology, Ukraine

Abstract

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.

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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

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15:15-15:45 Nucleotides, Ca2+ and the fate of neural stem cells

Professor Maria Abbrachio, University of Milan, Italy

Abstract

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.

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16:00-16:30 Calcium, memory and Alzheimer's disease

Professor Michael Berridge FRS, The Babraham Institute, UK

Abstract

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.

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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.

Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ
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