Adenosine Receptors: Expression, Function and Regulation

Sheth, Sandeep; Brito, Rafael; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, Vickram

doi:10.3390/ijms15022024

Cited by 326 publications

(307 citation statements)

References 168 publications

(217 reference statements)

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“…In clinical applications, ENT inhibitors might exert different effects in patients treated with AK inhibitors from A 1 receptor agonists. In addition, chronic activation of A 1 receptors reportedly influences the activities and/or expression levels of adenosine receptors and ENTs (Hettinger et al, 1998;Sheth et al, 2014;Hughes et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

An adenosine kinase inhibitor, ABT-702, inhibits spinal nociceptive transmission by adenosine release via equilibrative nucleoside transporters in rat

et al. 2015

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Adenosine kinase (AK) inhibitor is a potential candidate for controlling pain, but some AK inhibitors have problems of adverse effects such as motor impairment. ABT-702, a non-nucleoside AK inhibitor, shows analgesic effect in animal models of pain. Here, we investigated the effects of ABT-702 on synaptic transmission via nociceptive and motor reflex pathways in the isolated spinal cord of neonatal rats. The release of adenosine from the spinal cord was measured by HPLC. ABT-702 inhibited slow ventral root potentials (sVRPs) in the nociceptive pathway more potently than monosynaptic reflex potentials (MSRs) in the motor reflex pathway. The inhibitory effects of ABT-702 were mimicked by exogenously applied adenosine, blocked by 8CPT (8-cyclopentyl-1,3-dipropylxanthine), an adenosine A(1) receptor antagonist, and augmented by EHNA (erythro-9-(2-hydroxy-3-nonyl) adenine), an adenosine deaminase (ADA) inhibitor. Equilibrative nucleoside transporter (ENT) inhibitors reversed the effects of ABT-702, but not those of adenosine. ABT-702 released adenosine from the spinal cord, an effect that was also reversed by ENT inhibitors. The ABT-702-facilitated release of adenosine by way of ENTs inhibits nociceptive pathways more potently than motor reflex pathways in the spinal cord via activation of A1 receptors. This feature is expected to lead to good analgesic effects, but, caution may be required for the use of AK inhibitors in the case of ADA dysfunction or a combination with ENT inhibitors. (C) 2015 Elsevier Ltd. All rights reserved

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Section: Discussionmentioning

confidence: 99%

An adenosine kinase inhibitor, ABT-702, inhibits spinal nociceptive transmission by adenosine release via equilibrative nucleoside transporters in rat

et al. 2015

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“…Previous report indicates that the antidepressantlike effect of inosine may involve the activation of both A 1 and A 2A receptors [36]. However, it is also important to highlight that these receptors are able to interact, and other nonclassical transduction pathways might be operated under these conditions [77]. Therefore, additional studies will be required to explain the modulation of PKA activity by inosine and adenosine receptors.…”

Section: Discussionmentioning

confidence: 99%

Signaling pathways underlying the antidepressant-like effect of inosine in mice

Gonçalves

Neis

Rieger

et al. 2016

Purinergic Signalling

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Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A 1 and A 2A receptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca 2+ /calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3β) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) responsebinding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 μg/mouse, MEK1/2 inhibitor), KN-62 (1 μg/ mouse, CaMKII inhibitor), H-89 (1 μg/mouse, PKA inhibitor), and wortmannin (0.1 μg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a subeffective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 μg/mouse, GSK-3β inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3β. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression.

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“…This layout suggests that biosynthesis of adenosine from released ATP is positioned to favor a more important role of the nucleoside in suburothelial and detrusor muscle layers as compared to the urothelium where ecto-5′-nucleotidase/CD73 is almost absent if one excludes the basal cell layer [37]; see also preliminary results in the human bladder in [41]. Adenosine is a homeostatic metabolite in most organic systems mainly because it regulates neuronal excitability, vasodilation, smooth muscle relaxation, and release of vasoactive and neuroactive substances [42,43]; the nucleoside is also protective against ischemic and inflammatory insults. Therefore, we hypothesized that deficits in adenosine formation from released adenine nucleotides along with lifetime increments of ATP could contribute to detrusor overactivity in BPH patients.…”

Section: Discussionmentioning

confidence: 99%

Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder

Silva-Ramos

Silva

Faria

et al. 2015

Purinergic Signalling

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This study was designed to investigate whether reduced adenosine formation linked to deficits in extracellular ATP hydrolysis by NTPDases contributes to detrusor neuromodulatory changes associated with bladder outlet obstruction in men with benign prostatic hyperplasia (BPH). The kinetics of ATP catabolism and adenosine formation as well as the role of P1 receptor agonists on muscle tension and nerve-evoked [ ) or (2) extracellular adenosine accumulation with dipyridamole or EHNA, as these drugs inhibit adenosine uptake and deamination, respectively. In conclusion, reduced ATP hydrolysis leads to deficient adenosine formation and A 1 receptor-mediated inhibition of cholinergic nerve activity in the obstructed human bladder. Thus, we propose that pharmacological manipulation of endogenous adenosine levels and/or A 1 receptor activation might be useful to control bladder overactivity in BPH patients.

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Adenosine Receptors: Expression, Function and Regulation

Cited by 326 publications

References 168 publications

An adenosine kinase inhibitor, ABT-702, inhibits spinal nociceptive transmission by adenosine release via equilibrative nucleoside transporters in rat

An adenosine kinase inhibitor, ABT-702, inhibits spinal nociceptive transmission by adenosine release via equilibrative nucleoside transporters in rat

Signaling pathways underlying the antidepressant-like effect of inosine in mice

Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder

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