Evans AM (2020), On a Magical Mystery Tour with 8-Bromo-Cyclic A...

ECB-ART-49539

Molecules 2020 Oct 16;2520:. doi: 10.3390/molecules25204768.

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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.

Evans AM .

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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.

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	Figure 1. 8-Bromo-cyclic ADP-ribose.
	Figure 2. Schematic diagram that describes the two phases of hypoxic pulmonary vasoconstriction (HPV) triggered upon exposure of an isolated pulmonary artery ring to hypoxia. Phase 1 is driven by the smooth muscle (black). Phase 2 is driven by the smooth muscle (grey) and amplified through an endothelium-dependent mechanism (white).
	Figure 3. Example records show that the cADPR antagonist 8-bromo-cADPR (top left), ryanodine receptor block with ryanodine (bottom left) and depletion of sarcoplasmic reticulum calcium stores with cyclopiazonic acid (CPA; top right) attenuates (~60%) pulmonary artery dilation induced by Isoprenaline. Blocking BKCa channels with iberiotoxin delivers ~90% attenuation (bottom right).
	Figure 4. Example records show that pre-incubation of pulmonary artery rings with 8-bromo-cADPR, a cADPR antagonist, blocked phase 2, but not phase 1, of HPV (upper panels). By contrast, depletion of sarcoplasmic reticulum calcium stores with cyclopiazonic acid (CPA) blocked phase 1, but not phase 2, of HPV (lower panels).
	Figure 5. Pre-incubation of pulmonary artery rings with 8-bromo-cADPR blocks hypoxic pulmonary vasoconstriction (HPV) in an all-or-none manner (left hand panels). By contrast, when applied after prior induction of HPV in pulmonary arteries without endothelium, 8-bromo-cADPR reverses HPV in a concentration-dependent manner (right hand panel).
	Figure 6. Example cells showing labelling for SERCA2a (left hand series of panels) and SERCA2b (right hand series of panels) in pulmonary arterial myocytes. In each case, from left to right, a bright field image, z section, 3D reconstruction and 3D digital representation of labelling colour coded by region of the cell are shown. Nucleus identified by DAPI labelling (navy blue). Scale bar, 10 μm.
	Figure 7. Schematic representation of an early two compartment model developed to explain the curious pharmacology of 8-bromo-cADPR and cyclopiazonic acid.
	Figure 8. Example cells showing labelling for RyR1 (upper panels), RyR2 (middle panels) and RyR3 (lower panels) in pulmonary arterial myocytes. In each case, from left to right, a bright field image, 3D reconstruction and 3D digital representation of labelling colour coded by region of the cell are shown. Nucleus identified by DAPI labelling (navy blue). Scale bars, 10 μm.
	Figure 9. Example images showing lysosome-SR nanojunctions. Left hand image shows enlarged segment of an acutely isolated pulmonary arterial myocyte, that identifies nanojunctions (yellow) between LysoTracker Red labelled acidic stores and Bodipy-ryanodine positive SR in an acutely isolated pulmonary arterial myocyte. Dashed blue rectangle (vertical axis, 0.5 μm) identifies a Lysotraker Red labelled organelle and Bodipy-ryanodine labelled SR in the same focal plane, but separated by ~0.5 μm. Right hand panels show a brightfield image (left) and a 3D reconstruction (right) of a fixed cell labelled for lysosomes (αIGP120), RyR3 and the nucleus (DAPI, navy blue), that identifies lysosome-RyR3 clusters colour coded by region of the cell.
	Figure 10. Example cells showing labelling for SERCA1 (left hand panels) and RyR1 (right hand panels) in pulmonary arterial myocytes. In each case, upper panels show, from left to right, a bright field image, and 3D reconstructions with and without DAPI labelling (navy blue = nucleus). Lower panels show 3D digital representation of labelling colour coded by region of the cell. Scale bars, 10 μm.
	Figure 11. Upper panels show (from left to right) nuclear invaginations at differing orders of magnification, in sections through the nucleus of a pulmonary arterial myocyte in which the lumen of the sarcoplasmic reticulum has been loaded with Calcium Orange (Scale bars from left to right, 2 μm, 1 μm, 1 μm). Middle panels show ER tracker and Calcium Orange co-labelelling of nuclear invaginations. Draq5 identifies the nucleus (blue) in each case (Scale bars, 2 μm). Lower panel, electron micrograph shows nuclear invaginations in a pulmonary arterial myocyte in-situ in a pulmonary artery section (Scale bar, 2 μm).
	Figure 12. Fluo-4 fluorescence (green) identifies cytoplasmic nanocourses within the boundary of the Draq5 labelled nucleus (blue) of a confocal Z section through a pulmonary arterial myocyte (left hand panels i-iii). A spectral intensity plot across the nucleus (right hand panel iv) shows that nanocourses within nuclear invaginations (NI) exhibit higher levels of fluorescence than the nucleoplasm (N), and cytoplasm (C) identified by the dashed line in panel iii.
	Figure 13. From left to right, panels show pseudocolour representations of deconvolved z sections of Fluo-4 fluorescence that identify a cell-wide network of cytoplasmic nanocourses within three different acutely isolated pulmonary arterial myocytes, irrespective of cell size or shape. Right hand panels show enlarged images of two cytoplasmic nanocourses from the same cell, in which asynchronous, time-dependent fluctuations in hotspots of calcium flux (from top to bottom) can be seen.
	Figure 14. Upper panels, from left to right, show myocyte relaxation in response to RyR1 activation by maurocalcine, with nanocourse-specific changes in calcium flux identified in pseudocolour representations of deconvolved z sections of Fluo-4 fluorescence (scale bar, 2 μm). Lower left, panels similarly show calcium flux during myocyte contraction induced by angiotensin II (scale bar, 3 μm). Lower right, panels show angiotensin II-induced increases in calcium flux within nuclear nanocourses of a different cell (scale bar, 1 μm).
	Figure 15. Right hand panels, sections through a 3D reconstruction of the nucleus of a pulmonary arterial myocyte reveal puncta of lamin A and H3K9me2 colocalisation on a lamin A positive transnuclear invagination (from left to right scale bars 1 μm, 1 μm, 500 nm). Left hand panels, sections similarly show puncta of emerin and BAF (barrier to autointegration factor) colocalisation on transnuclear and blind invaginations (from left to right scale bars 1 μm, 1 μm, 500 nm).
	Figure 16. Calcium signalling is analogous to quantum tunneling across a cell-wide circuit with the nucleus at its centre. (a) and (b), Microprocessor at the centre of a circuit board. (c) (Fluo-4, green) and (d) (Fluo-4, pseudocolour), show the nucleus (Draq5 in (c) only, blue) at the centre of a cell-wide circuit of cytoplasmic nanocourses. e, Schematic shows calcium flux across cytoplasmic nanocourses demarcated by junctions between the plasma membrane and sarcoplasmic reticulum (PM-SR nanojunction), the sarcoplasmic reticulum nanojunctions aligned with the contractile myofilaments of a smooth muscle and the nuclear invaginations. Angiotensin II, AngII; Ryanodine receptor, RyR; Sarco/endoplasmic reticulum calcium ATPase, SERCA; sodium/calcium exchanger, NCX; ADP-ribosyl cyclase, ARC; Myosin light chain kinase, MLCK; AT1, Angiotensin AT1 receptor; Protein kinase A PKA; large conductance calcium-activated potassium channel, BKCa. Panels (a) and (b) are free images. The schematic in panel (e) was adapted from previous versions developed and published by AME. Reprinted from Publication title, Vol /edition number, Author(s), Title of article / title of chapter, Pages No., Advances in Pharmacology, 78, Evans AM, Nanojunctions of the Sarcoplasmic Reticulum Deliver Site- and Function-Specific Calcium Signaling in Vascular Smooth Muscles, 1–47 Copyright (2017), with permission from Elsevier.

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