Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We must value diversity not only in words, but also in actions.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The P2X7 receptor is a cell surface ligand-gated ion channel, activated by its physiological nucleotide agonist ATP and a synthetic analogue (BzATP). However, it has also been suggested that there ...may be structurally unrelated, non-nucleotide agonists such as the amyloidogenic β peptide. Here we aimed to reassess the effect of amyloid β peptides in various in vitro cell models, namely HEK293 overexpressing human P2X7, the microglial BV-2 cell line, and BV-2 cells lacking P2X7. We measured YO-PRO-1 dye uptake in response to full-length amyloid β peptide (1-42) or the shorter amyloid β peptide (25-35) and there was a concentration-dependent increase in YOPRO-1 dye uptake in HEK-hP2X7 cells. However, these amyloid β peptide-induced increases in YOPRO-1 dye uptake were also identical in non-transfected HEK-293 cells. We could observe small transient increases in Ca2+i induced by amyloid β peptides in BV-2 cells, however these were identical in BV-2 cells lacking P2X7. Furthermore, our metabolic viability and LDH release experiments suggest no significant change in viability or cell membrane damage in HEK-hP2X7 cells. In the BV-2 cells we found that high concentrations of amyloid β peptides (1-42) and (25-35) could reduce cell viability by up to 35% but this was also seen in BV-2 cells lacking P2X7. We found no evidence of LDH release by amyloid β peptides. In summary, we found no evidence that amyloid β peptides act as agonists of P2X7 in our in vitro models. Our study raises the possibility that amyloid β peptides simply mimic features of P2X7 activation.
The family of ligand-gated ion channels known as P2X receptors were discovered several decades ago. Since the cloning of the seven P2X receptors (P2X1-P2X7), a huge research effort has elucidated ...their roles in regulating a range of physiological and pathophysiological processes. Transgenic animals have been influential in understanding which P2X receptors could be new therapeutic targets for disease. Furthermore, understanding how inherited mutations can increase susceptibility to disorders and diseases has advanced this knowledge base. There has been an emphasis on the discovery and development of pharmacological tools to help dissect the individual roles of P2X receptors and the pharmaceutical industry has been involved in pushing forward clinical development of several lead compounds. During the discovery phase, a number of positive allosteric modulators have been described for P2X receptors and these have been useful in assigning physiological roles to receptors. This review will consider the major physiological roles of P2X1-P2X7 and discuss whether enhancement of P2X receptor activity would offer any therapeutic benefit. We will review what is known about identified compounds acting as positive allosteric modulators and the recent identification of drug binding pockets for such modulators.
A Diverse View of Science to Catalyse Change Urbina-Blanco, César A; Jilani, Safia Z; Speight, Isaiah R ...
Journal of the American Chemical Society,
08/2020, Volume:
142, Issue:
34
Journal Article
Peer reviewed
Open access
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IJS, KILJ, NUK, PNG, UL, UM
Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We can value diversity not only in words, but also in actions.
Full text
Available for:
IJS, KILJ, NUK, UL, UM, UPUK
Adenosine 5'-triphosphate is a well-known extracellular signaling molecule and neurotransmitter known to activate purinergic P2X receptors. Information has been elucidated about the structure and ...gating of P2X channels following the determination of the crystal structure of P2X4 (zebrafish), however, there is still much to discover regarding the role of this receptor in the central nervous system (CNS). In this review we provide an overview of what is known about P2X4 expression in the CNS and discuss evidence for pathophysiological roles in neuroinflammation and neuropathic pain. Recent advances in the development of pharmacological tools including selective antagonists (5-BDBD, PSB-12062, BX430) and positive modulators (ivermectin, avermectins, divalent cations) of P2X4 will be discussed.
The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically ...on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A2A receptor (A2A R) and cannabinoid CB1 receptor (CB1 R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A2A R and CB1 R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A2A R-CB1 R heteromeric complexes. However, the specific location and properties of these heteromers have remained largely unknown. Here, by using techniques that allowed a precise visualization of the heteromers in situ in combination with sophisticated genetically modified animal models, together with biochemical and pharmacological approaches, we provide a high-resolution expression map and a detailed functional characterization of A2A R-CB1 R heteromers in the dorsal striatum. Specifically, our data unveil that the A2A R-CB1 R heteromer (i) is essentially absent from corticostriatal projections and striatonigral neurons, and, instead, is largely present in striatopallidal neurons, (ii) displays a striking G protein-coupled signaling profile, where co-stimulation of both receptors leads to strongly reduced downstream signaling, and (iii) undergoes an unprecedented dysfunction in Huntington's disease, an archetypal disease that affects striatal neurons. Altogether, our findings may open a new conceptual framework to understand the role of coordinated adenosine-endocannabinoid signaling in the indirect striatal pathway, which may be relevant in motor function and neurodegenerative diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Learning to lead Bibic, Lucka
Science (American Association for the Advancement of Science),
2018-Sep-14, 2018-09-14, 20180914, Volume:
361, Issue:
6407
Journal Article
A diverse view of science to catalyse change Urbina-Blanco, César A; Jilani, Safia Z; Speight, Isaiah R ...
Chemical science (Cambridge),
09/2020, Volume:
11, Issue:
34
Journal Article
Peer reviewed
Open access
Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We can value diversity not only in words, but also in actions.
...Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We must value diversity not only in words, but also in actions.
Full text
Available for:
IJS, KILJ, NUK, UL, UM, UPUK
A Diverse View of Science to Catalyse Change Urbina‐Blanco, César A.; Jilani, Safia Z.; Speight, Isaiah R. ...
Angewandte Chemie,
October 12, 2020, Volume:
132, Issue:
42
Journal Article
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