AMP Is an Adenosine A1 Receptor Agonist

Rittiner, Joseph E.; Korboukh, Ilia; Hull-Ryde, Emily A.; Jin, Jian; Janzen, William P.; Frye, Stephen V.; Zylka, Mark J.

doi:10.1074/jbc.m111.291666

Cited by 117 publications

(121 citation statements)

References 48 publications

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“…Very recent data obtained in transfected tumor cells indicate that AMP is a specific ligand of A1R. 28 Remarkably, 5 0 -NT appears the only enzyme responsible for extracellular degradation of AMP into Ado, 19 and its expression levels are quite low in most areas of the brain. 30 These findings suggest that the enzyme is constitutively limiting rate of Ado formation from AMP, a condition that may favor extraneuronal accumulation of the nucleotide, and ensuing A1R activation within specific brain regions.…”

Section: Discussionmentioning

confidence: 99%

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Muzzi

Blasi

Masi

et al. 2012

J Cereb Blood Flow Metab

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Therapeutic hypothermia is of relevance to treatment of increased body temperature and brain injury, but drugs inducing selective, rapid, and safe cooling in humans are not available. Here, we show that injections of adenosine 5 0 -monophosphate (AMP), an endogenous nucleotide, promptly triggers hypothermia in mice by directly activating adenosine A1 receptors (A1R) within the preoptic area (POA) of the hypothalamus. Inhibition of constitutive degradation of brain extracellular AMP by targeting ecto 5 0 -nucleotidase, also suffices to prompt hypothermia in rodents. Accordingly, sensitivity of mice and rats to the hypothermic effect of AMP is inversely related to their hypothalamic 5 0 -nucleotidase activity. Single-cell electrophysiological recording indicates that AMP reduces spontaneous firing activity of temperature-insensitive neurons of the mouse POA, thereby retuning the hypothalamic thermoregulatory set point towards lower temperatures. Adenosine 5 0 -monophosphate also suppresses prostaglandin E2-induced fever in mice, having no effects on peripheral hyperthermia triggered by dioxymetamphetamine (ecstasy) overdose. Together, data disclose the role of AMP, 5 0 -nucleotidase, and A1R in hypothalamic thermoregulation, as well and their therapeutic relevance to treatment of febrile illness.

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Section: Discussionmentioning

confidence: 99%

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Muzzi

Blasi

Masi

et al. 2012

J Cereb Blood Flow Metab

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“…It has been recently reported that 5 0 -AMP can bind with a high affinity to A 1 R on HEK293 cells, 10 raising the question whether this nucleotide could deliver immunomodulatory signals to B cells. We observed that the treatment of in vitroactivated B cells with eATP plus AMPCP (a CD73 inhibitor) in order to prevent 5 0 -AMP utilization and increase its concentration in culture, did not have adverse effects on CD39 high B-cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…14 Nevertheless, these B cells inhibit T-cell proliferation and cytokine production by a mechanism presumably driven by 5 0 -AMP signaling. 14 As 5 0 -AMP was reported to be an A 1 R agonist, 10 we surmise that functions of A 1 R C T cells are inhibited not only by ADO via A 2A R but also by B cell-derived 5 0 -AMP signaling via the A 1 R. The molecular mechanisms involved in the ATP-driven suppression of T-cell functions by B cells remain poorly understood, and the identity of Breg responsible for this effect and their characteristics remain unclear. In fact, the precise Breg phenotype has been elusive and seems to be species dependent and modulated by environmental or contextual cellular interactions.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 The role of A 1 R or A 3 R in ADO-mediated immune regulation is not entirely clear, although 5 0 -AMP was reported to be an A 1 R agonist with affinity equal to or better than that of ADO. 10 In cancer, ADO is viewed as a pro-tumor factor which suppresses antitumor functions of Teff and promotes functions of suppressor cells (Treg and MDSC). 11,12 Generally, B cells are viewed as promoters of T-cell activation and proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

et al. 2016

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CD39 and CD73 are key enzymes in the adenosine (ADO) pathway. ADO modulates pathophysiological responses of immune cells, including B cells. It has recently emerged that a subpopulation of ADOproducing CD39 C CD73 C B cells has regulatory properties. Here, we define the CD39 high subset of these cells as the major contributor to the regulatory network operated by human B lymphocytes. Peripheral blood B cells were sorted into CD39 neg , CD39 inter and CD39 high subsets. The phenotype, proliferation and IL-10 secretion by these B cells were studied by flow cytometry. 5 0 -AMP and ADO levels were measured by mass spectrometry. Agonists or antagonists of A 1 R, A 2A R and A 3 R were used to study ADO-

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“…Furthermore, reconstitution of CD73-deficient mice with soluble CD73 restored injury, and wild-type mice pre-treated with CD73 inhibitor were protected. We speculate that the accumulation of extracellular AMP could exert a protective effect in mild renal IRI, possibly via the A 1 R given the recent identification of AMP as a ligand for this receptor [66].…”

Section: Adenosine 1 Receptor (A 1 R)mentioning

confidence: 99%

The CD39-adenosinergic axis in the pathogenesis of renal ischemia–reperfusion injury

Roberts

Lü

Rajakumar

et al. 2012

Purinergic Signalling

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Hypoxic injury occurs when the blood supply to an organ is interrupted; subsequent reperfusion halts ongoing ischemic damage but paradoxically leads to further inflammation. Together this is termed ischemia-reperfusion injury (IRI). IRI is inherent to organ transplantation and impacts both the short-and long-term outcomes of the transplanted organ. Activation of the purinergic signalling pathway is intrinsic to the pathogenesis of, and endogenous response to IRI. Therapies targeting the purinergic pathway in IRI are an attractive avenue for the improvement of transplant outcomes and the basis of ongoing research. This review aims to examine the role of adenosine receptor signalling and the ecto-nucleotidases, CD39 and CD73, in IRI, with a particular focus on renal IRI. Ischemia-reperfusion injury (IRI) is an obligatory insult in transplantation occurring at the time of organ procurement and engraftment. Ischemia is induced when blood flow to an organ is interrupted. Re-establishment of blood flow is essential to prevent ongoing hypoxic injury but paradoxically imparts further injury, termed IRI. Warm ischemia is relatively short in brain dead donors (<30 min); however, this can be prolonged in donors following cardiac arrest (up to 90 min). Furthermore, unique to transplantation is the period of cold preservation, which slows the cellular metabolic rate in order to minimize ongoing ischemic damage but which may be prolonged (extending to hours). The clinical ramifications of IRI include systemic inflammatory effects and organ dysfunction, increasing graft immunogenicity, the risk of delayed graft function, acute rejection, and chronic allograft dysfunction. There is substantial evidence implicating purinergic signalling in both the pathogenesis of and the endogenous response to IRI, and strategies targeting various aspects of the pathway may therefore be of therapeutic potential. ATP, present in relatively high concentrations intracellularly, is extruded from injured and necrotic cells into the extracellular space or released in a more controlled manner from apoptotic cells through pannexin hemi-channels and from inflammatory cells via connexin hemi-channels [1]. Upon release, extracellular ATP acts in an autocrine or paracrine manner on specific cell-surface P2 receptors belonging to two subclasses, the G protein-coupled P2Y receptors and the ATP-gated P2X nonselective cation channels [2]. ATP Keywords

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AMP Is an Adenosine A1 Receptor Agonist

Cited by 117 publications

References 48 publications

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

The CD39-adenosinergic axis in the pathogenesis of renal ischemia–reperfusion injury

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AMP Is an Adenosine A1 Receptor Agonist

Cited by 117 publications

References 48 publications

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

The CD39-adenosinergic axis in the pathogenesis of renal ischemia–reperfusion injury

Contact Info

Product

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Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)