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On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: from All-Or-None Block to Nanojunctions and the Cell-Wide Web

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On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: from All-Or-None Block to Nanojunctions and the Cell-Wide Web molecules Review On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: From All-or-None Block to Nanojunctions and the Cell-Wide Web A. Mark Evans Centre for Discovery Brain Sciences and Cardiovascular Science, Edinburgh Medical School, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, UK; [email protected] Academic Editors: Marie Migaud and Gerd Wagner Received: 25 August 2020; Accepted: 8 September 2020; Published: 16 October 2020 Abstract: A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors facilitated inositol-1,4,5-trisphosphate (IP3) production, activation of IP3 receptors and thus calcium release from S/ER. Adding to this, it was evident that S/ER resident ryanodine receptors (RyRs) could support two opposing cellular functions by delivering either highly localised calcium signals, such as calcium sparks, or by carrying propagating, global calcium waves. Coincidentally, it was reported that RyRs in mammalian cardiac myocytes might be regulated by a novel calcium mobilising messenger, cyclic adenosine diphosphate-ribose (cADPR), that had recently been discovered by HC Lee in sea urchin eggs. A reputedly selective and competitive cADPR antagonist, 8-bromo-cADPR, had been developed and was made available to us. We used 8-bromo-cADPR to further explore our observation that S/ER calcium release via RyRs could mediate two opposing functions, namely pulmonary artery dilation and constriction, in a manner seemingly independent of IP3Rs or calcium influx pathways. Importantly, the work of others had shown that, unlike skeletal and cardiac muscles, smooth muscles might express all three RyR subtypes. If this were the case in our experimental system and cADPR played a role, then 8-bromo-cADPR would surely block one of the opposing RyR-dependent functions identified, or the other, but certainly not both. The latter seemingly implausible scenario was confirmed. How could this be, do cells hold multiple, segregated SR stores that incorporate different RyR subtypes in receipt of spatially segregated signals carried by cADPR? The pharmacological profile of 8-bromo-cADPR action supported not only this, but also indicated that intracellular calcium signals were delivered across intracellular junctions formed by the S/ER. Not just one, at least two. This article retraces the steps along this journey, from the curious pharmacological profile of 8-bromo-cADPR to the discovery of the cell-wide web, a diverse network of cytoplasmic nanocourses demarcated by S/ER nanojunctions, which direct site-specific calcium flux and may thus coordinate the full panoply of cellular processes. Keywords: 8-bromo-cADPR; cADPR; calcium; hypoxic pulmonary vasoconstriction; sarcoplasmic reticulum; KV7; ryanodine receptor; two pore channel 2; arterial smooth muscle; nanojunction; nanospace; nanocourse; nucleus; nuclear invagination 1. Introduction Cells select for one or a combination of distinct functions through calcium signalling. Therefore, stimuli must induce different calcium signals to select for one or other of a variety of specific cellular processes, such as cell activation, inhibition and proliferation, which additionally requires changes in gene expression [1]. A variety of highly specialised, intracellular ion channels evolved for this Molecules 2020, 25, 4768; doi:10.3390/molecules25204768 www.mdpi.com/journal/molecules Molecules 2020, 25, 4768 2 of 39 Molecules 2020, 25, 4768 2 of 39 processes, such as cell activation, inhibition and proliferation, which additionally requires changes purposein gene [2expression,3]. However, [1]. A despite variety the of extraordinarily highly specialised, detailed intracellular mapping ion of thechannels temporal evolved characteristics for this ofpurpose both unitary [2,3]. However, and macroscopic despite calciumthe extraordinarily signals across detailed a variety mapping of cell of typesthe temporal [4–10], howcharacteristics cells deliver theof diverseboth unitary range and of site-macroscopic and function-specific calcium signals calcium across signalsa variety necessary of cell types to coordinate [4–10], how the cells full deliver panoply the diverse range of site- and function-specific calcium signals necessary to coordinate the full of cellular processes remains enigmatic [11,12]. panoply of cellular processes remains enigmatic [11,12]. The primary intracellular calcium store is the sarco/endoplasmic reticulum (S/ER), which forms a The primary intracellular calcium store is the sarco/endoplasmic reticulum (S/ER), which forms contiguous organelle from its origin at the outer nuclear membrane to the periphery of all cells [13]. a contiguous organelle from its origin at the outer nuclear membrane to the periphery of all cells [13]. Calcium signals with clear diversities of form and function are delivered via the S/ER, in a manner that Calcium signals with clear diversities of form and function are delivered via the S/ER, in a manner meets the specific functional requirements of a given cell type [6,7,10,12,14]. Irrespective of cell type the that meets the specific functional requirements of a given cell type [6,7,10,12,14]. Irrespective of cell currenttype the consensus current consensus is that within is that a wide, within open a wide, cytoplasm open highlycytoplasm localised highly calcium localised signals calcium (e.g., signals calcium sparks)(e.g., calcium direct region-specific sparks) direct functions,region-specific while functions, propagating while global propagating calcium signals global coordinate calcium signals primary cell-specificcoordinate functionsprimary cell-specific (e.g., muscle functions contraction, (e.g., secretion).muscle contraction, Adding secretion). to this, adjustments Adding to tothis, gene expressionadjustments are to presumedgene expression to be are governed presumed by variationsto be governed in the by spatiotemporalvariations in the patterns spatiotemporal of global calciumpatterns transients of global that calcium gain unrestrictedtransients that entry gain to theunrestricted nucleoplasm entry across to the the nucleoplasm nuclear envelope across andthe its invaginationsnuclear envelope [15– 19and]. its invaginations [15–19]. ThisThis reviewreview willwill retrace the the steps steps in in the the development development and and testing testing of a ofnovel a novel hypothesis hypothesis on the on themechanism mechanism of ofintracellular intracellular calcium calcium signalling, signalling, that that was was first first prompted prompted by bythe the very very peculiar peculiar pharmacologypharmacology ofof 8-bromo-cyclic8-bromo-cyclic adenosine diphos diphosphate-ribosephate-ribose (8-bromo-cADPR; (8-bromo-cADPR; Figure Figure 1)1 [20].)[ 20 ]. Importantly,Importantly, 8-bromo-cADPR 8-bromo-cADPR hadhad beenbeen proposed to to be be a a competitive competitive antagonist antagonist of of cyclic cyclic adenosine adenosine diphosphate-ribosediphosphate-ribose (cADPR), (cADPR), a novel a novel calcium calcium mobilising mobilising pyridine nucleotidepyridine [21nucleotide]. The pharmacological [21]. The profilepharmacological of 8-bromo-cADPR profile of of8-brom whicho-cADPR I speak wasof which at first I speak sight was surprising, at first sight but then surprising, became but curiouser, then andbecame curiouser curiouser, still. and There curiouser seemed still. to beThere one seem explanationed to be forone outcomesexplanation and for one outcomes explanation and one only, thatexplanation different calciumonly, that signals different must calcium be delivered signals bymust diff beerent delivered SR compartments, by different SR into compartments, functionally distinct into cytoplasmicfunctionally spaces,distinct somehowcytoplasmic demarcated spaces, somehow by junctions demarcated formed by junctions by the SR formed [11,22 by–25 the]. SR Our [11,22– further studies25]. Our ultimately further studies led to ultimately the discovery led to of the the discovery cell-wide of web,the cell-wide a network web, of a cytoplasmicnetwork of cytoplasmic nanocourses demarcatednanocourses by demarcated S/ER, which by S/ER, direct which calcium direct signals calciu inm asignals manner in a that manner may that be sumayfficient be sufficient to allow to for stimulus-specifiedallow for stimulus-specified coordination coordination of the full of panoply the full ofpanoply cellular of processes. cellular processes. Figure 1. 8-Bromo-cyclic8-Bromo-cyclic ADP-ribose. ADP-ribose. However,However, the the path path toto thethe cell-widecell-wide web did did not not begin begin with with considerations considerations on on calcium calcium signalling signalling perper se se,, but but with with the the discoverydiscovery ofof aa novelnovel potassium cu currentrrent in in acutely acutely isolated isolated pulmonary pulmonary arterial arterial smooth muscle cells. Therefore, in order to understand the “logic” of each step along this experimental road, the story must begin here. Molecules 2020, 25, 4768 3 of 39 2. A Tale of Two Channels and Perhaps a Few Dollars More During 1994 I was tasked with characterising potassium channels in porcine pulmonary arterial myocytes, with the aim of determining whether, as postulated, exposure to hypoxia during the perinatal period altered normal developmental changes in potassium currents (kinetics
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