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For Review Only Local and regional control of calcium dynamics in the pancreatic islet Journal: Diabetes, Obesity and Metabolism ManuscriptFor ID DOM-17-0216-SUP.R1 Review Only Manuscript Type: Supplement Article Date Submitted by the Author: n/a Complete List of Authors: Rutter, Guy; Imperial College London, Cell Biology Hodson, David; University of Birmingham, Institute of Metabolism and Systems Research Chabosseau, Pauline; Imperial College London, Cell Biology Haythorne, Elizabeth; Imperial College London, Cell Biology Pullen, Timothy; Imperial College London, Cell Biology Leclerc, Isabelle; Imperial College London, Cell Biology Key Words: beta cell, insulin secretion, islets, type 2 diabetes Page 1 of 26 1 2 th 3 Diabetes, Obesity and Metabolism. April 19 , 2017.R1 4 5 6 7 Local and regional control of calcium dynamics in the pancreatic islet 8 9 10 1 2 1 1 1 11 Guy A. Rutter *, David J. Hodson *, Pauline Chabosseau , Elizabeth Haythorne , Timothy J. Pullen 1 12 and Isabelle Leclerc 13 14 15 1 16 Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and 17 Metabolism, Department of Medicine, and the Imperial Pancreatic Islet Biology and Diabetes Consortium, Hammersmith Hospital, Imperial College London, du Cane Road, London W12 ONN, 18 2 19 U.K., and Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, B15 2TT, UK.,For Centre Reviewfor Endocrinology, Diabetes Only and Metabolism, Birmingham Health 20 Partners, Birmingham, B15 2TH, UK., COMPARE University of Birmingham and University of 21 Nottingham Midlands, UK. 22 23 Running Title: Islet Ca2+ dynamics 24 25 26 *Correspondence: [email protected] or [email protected] 27 Callouts (3): embedded 28 29 4,866/7,000 words (exc. figure legends and references), 4 figs, 1 Table, 107/100 refs 30 31 Keywords: insulin; Ca2+; organelle; connectivity; imaging 32 33 2+ 2+ Abbreviations: CICR, Ca induced Ca release; GFP, green fluorescent protein; IP3, inositol 1,4,5 34 trisphosphate; K , ATPdependent K+ channel; MCUa, mitochondrial uniporter a; NCX, Na+/Ca2+ 35 ATP exchanger; PMCA, plasma membrane Ca2+ ATPase; RyR, ryanodine receptor; SERCA, 36 2+ 2+ 37 sarco(endo)plasmic reticulum Ca ATPase; T2D, type 2 diabetes; VDCC, voltage-dependent Ca 38 channel 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 59 60 Page 2 of 26 1 2 3 Abstract 4 2+ 5 Ca is the key intracellular regulator of insulin secretion, acting in the beta cell as the ultimate trigger + 6 for exocytosis. In response to high glucose, ATPsensitive K channel closure and plasma membrane 7 depolarisation engage a sophisticated machinery to drive pulsatile cytosolic Ca2+ changes. Voltage- 8 gated Ca2+ channels, Ca2+-activated K+ channels and Na+/Ca2+ exchange all play important roles. The 9 use of targeted Ca2+ probes has revealed that during each cytosolic Ca2+ pulse, uptake of Ca2+ by 10 2+ mitochondria, endoplasmic reticulum (ER), secretory granules and lysosomes fine-tune cytosolic Ca 11 dynamics and control organellar function. For example, changes in the expression of the Ca2+ binding 12 2+ 13 protein Sorcin appear to provide a link between ER Ca levels and ER stress, affecting beta cell 14 function and survival. Across the islet, intercellular communication between highly interconnected 15 “hubs”, which act as pacemaker beta cells, and subservient “followers”, ensures efficient insulin 16 secretion. Loss of connectivity is seen after the deletion of genes associated with type 2 diabetes 17 (T2D) and follows metabolic and inflammatory insults that characterize this disease. Hubs, which 18 typically comprise ~1-10 % of total beta cells, are repurposed for their specialized role by expression 19 of high glucokinase (GckFor) but lower Review Pdx1 and Nkx6.1 levels. Only Single cell -omics are poised to provide 20 21 a deeper understanding of the nature of these cells and of the networks through which they 2+ 22 communicate. New insights into the control of both the intra- and intercellular Ca dynamics may 23 thus shed light on T2D pathology and provide novel opportunities for therapy. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 2 59 60 Page 3 of 26 1 2 3 Introduction 4 2+ 5 A likely role for Ca in the control of insulin secretion was first shown by experiments 6 demonstrating that the release of the hormone in response to fuel secretagogues was blocked in the 7 absence of these ions [1] (and references therein). A role for Ca2+ as a cardinal trigger for secretion 8 was later enshrined in the “consensus” model of glucose-induced insulin secretion, which involves 9 activation of glycolytic and mitochondrial ATP synthesis, closure of ATPsensitive K+ channels 10 2+ 2+ (KATP), plasma membrane depolarisation and Ca influx through voltage-dependent Ca channels 11 2+ 12 (VDCC) [2] (Fig. 1). The contributions of intracellular Ca transport pathways, and of other 13 intracellular ion channels, in the generation of these signals remains more controversial, and will be 14 discussed later. 15 2+ 16 Our focus in this contribution will thus be the role and regulation of Ca dynamics in and 17 between beta cells. For a more comprehensive review of the role of these ions in the regulation of 18 secretion from other islet neuroendocrine cells, the reader is referred to recent articles, e.g. [3,4]. 19 For Review Only 20 Key technical developments in Ca2+ signalling 21 22 A full appreciation of the control and likely importance of glucose-triggered intracellular Ca2+ 23 changes in beta cells was significantly enhanced by the development by Tsien and colleagues [5] of 24 chemically-synthesized, low molecular weight and intracellularly-trappable dyes such quin-2 [6] and 25 later fura-2 [7-9]. These optical probes allowed fluctuations in free Ca2+ to be reported in real time in 26 single living cells and, subsequently, at the subcellular level, though fluorescence imaging. This 27 28 technique thus allowed the elaboration of earlier biochemical studies, based on the use of 45 + 2+ 2+ 29 radioisotopes such as Ca, and revealed, for example, the importance of Na /Ca exchange in Ca 2+ 30 extrusion [10], as well as regionalisation of Ca responses to glucose and other stimuli [8]. 31 2+ 32 A limitation of the above class of probes is, however, that they do not usually allow Ca to be 33 measured selectively in subcellular organelles. This restricts studies aimed at understanding the 34 molecular mechanisms (transporters, channels etc) which mediate Ca2+ flux across the relevant 35 membranes. Alternative probes, developed shortly after the fluorescent reporters, by Pozzan and 36 Rizzuto [11], and deployed by us and others in beta cells [9,12,13], exploited instead natural 37 bioluminescent sensors, such as aequorin from the jellyfish Aequoria victoria. Whilst in earlier studies 38 39 these proteins had been purified and introduced directly into cells, for example after skinning of 40 muscle fibres [14], the development of recombinant technologies meant they could be expressed from 41 the corresponding cDNA. Importantly, after fusion of these cDNAs with those encoding suitable 42 targeting sequences, the bioluminescent probes could be targeted directly to selected subcellular 43 locations. The targeting domains usually involved short peptide sequences or, in some cases, a full 44 length protein [13,15]. Transfection with the corresponding plasmids (or expression from viral 45 constructs), and reconstitution with the prosthetic group coelenterazine, was then coupled to suitable 46 47 (and usually highly sensitive) detection systems: a simple photomultiplier tube usually sufficed [16], 48 though subsequent developments used in-sequence photocathode arrays for imaging [17]. 49 50 The first chimaeric probe to be used in this way in beta cells was an aequorin, linked to the 51 leader sequence of mitochondrial cytochrome c oxidase subunit VIII [18], thus localising it to the 52 mitochondrial matrix [9]. Probes targeted to the endoplasmic reticulum (ER) and Golgi [19], as well 53 as secretory granules [19], were subsequently deployed, and will be discussed in more detail below. 54 Although later superseded by more sensitive fluorescent recombinant probes based on green 55 fluorescent protein (GFP) [3,20], much of our current knowledge of organellar Ca2+ dynamics in beta 56 57 58 3 59 60 Page 4 of 26 1 2 2+ 3 cells was based on the use of the above. GFPbased probes, in contrast, rely on Ca -induced changes 4 either in the intrinsic fluorescence of the GFP backbone (created by the introduction of a Ca2+ sensing 5 domain onto a circularly-permuted fluorophore) or the Ca2+-dependent change on the interaction 6 between two spectrally-shifted GFP variants (Förster resonance energy transfer; FRET), again 7 controlled by Ca2+ binding to peptide linking the pair. Table 1 provides a list of chemical and 8 recombinant Ca2+ probes and examples of their use in beta cells (or other tissue where information is 9 10 not available). 11 12 The following section summarises the key findings made using the above targeted probes in 13 beta cells. These are summarized in Figure 1. 14 2+ 15 Localisation of glucose-induced Ca changes in beta cells 16 Cytoplasmic Ca2+ levels in beta cells are maintained via a complex interplay between Ca2+ 17 2+ 18 entry (predominantly through VDCC), Ca uptake and release from/into intracellular stores, 2+ 2+ 19 organelles and secretoryFor granules, Review and Ca extrusion Onlyvia plasma membrane pumps (e.g. Ca 20 ATPase) and exchangers (e.g. Na+/Ca2+ exchanger). Alteration at any point in this regulatory cascade 21 – either as a result of changes in energy metabolism and hence KATP channel closure, or in the 22 expression or post-translational modification of Ca2+ channels/pumps/exchangers – will lead to 23 alterations in beta cell Ca2+ concentration, with knock-on effects for insulin release.
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