Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain

Lemos, Cristina; Pinheiro, Bárbara S.; Beleza, Rui O.; Marques, Joana M.; Rodrigues, Ricardo J.; Cunha, Rodrigo A.; Rial, Daniel; Köfalvi, Attila

doi:10.1007/s11302-015-9474-3

Cited by 21 publications

(18 citation statements)

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“…18 Adenosine can also increase glucose uptake in mouse neurons and astrocytes via activation of the adenosine 2B receptor. 34 In conclusion, our data do not support a role for AMPK in acutely regulating ATP release from astrocytes. Instead, we find that complete loss of AMPK activity, mediated by knockout of both catalytic subunits, reduced eATP levels by reducing intracellular ATP levels.…”

Section: Discussioncontrasting

confidence: 76%

“…ATP can be broken down in the extracellular space to form adenosine and recent evidence suggests that astrocyte‐derived adenosine (released as ATP) can reduce food intake via activation of AgRP neuron adenosine A1 receptors . Adenosine can also increase glucose uptake in mouse neurons and astrocytes via activation of the adenosine 2B receptor …”

Section: Discussionmentioning

confidence: 99%

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AMP‐activated protein kinase (AMPK) activator A‐769662 increases intracellular calcium and ATP release from astrocytes in an AMPK‐independent manner

Walker

Robb

et al. 2017

Diabetes Obesity Metabolism

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Aim:To test the hypothesis that, given the role of AMP-activated protein kinase (AMPK) in regulating intracellular ATP levels, AMPK may alter ATP release from astrocytes, the main sources of extracellular ATP (eATP) within the brain. Materials and Methods:Measurements of ATP release were made from human U373 astrocytoma cells, primary mouse hypothalamic (HTAS) and cortical astrocytes (CRTAS) and wild-type and AMPK α1/α2 null mouse embryonic fibroblasts (MEFs). Cells were treated with drugs known to modulate AMPK activity: A-769662, AICAR and metformin, for up to 3 hours. Intracellular calcium was measured using Fluo4 and Fura-2 calcium-sensitive fluorescent dyes. Results:In U373 cells, A-769662 (100 μM) increased AMPK phosphorylation, whereas AICAR and metformin (1 mM) induced a modest increase or had no effect, respectively. Only A-769662 increased eATP levels, and this was partially blocked by AMPK inhibitor Compound C.A-769662-induced increases in eATP were preserved in AMPK α1/α2 null MEF cells. A-769662 increased intracellular calcium in U373, HTAS and CRTAS cells and chelation of intracellular calcium using BAPTA-AM reduced A-769662-induced eATP levels. A-769662 also increased ATP release from a number of other central and peripheral endocrine cell types. Conclusions:AMPK is required to maintain basal eATP levels but is not required for A-769662-induced increases in eATP. A-769662 (>50 μM) enhanced intracellular calcium levels leading to ATP release in an AMPK and purinergic receptor independent pathway. K E Y W O R D SA-769662, AMPK, ATP, BV-2, C2C12, cortical astrocytes, GT1-7, H4IIE, hypothalamic astrocytes, INS-1, intracellular calcium, SH-SY5Y, U373

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Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

AMP‐activated protein kinase (AMPK) activator A‐769662 increases intracellular calcium and ATP release from astrocytes in an AMPK‐independent manner

Walker

Robb

et al. 2017

Diabetes Obesity Metabolism

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“…; Lemos et al . ; Duarte et al . ), calcium waves (Kawamura and Kawamura ; Kanno and Nishizaki ) and the ability of astrocytes to uptake neurotransmitters (Nishizaki et al .…”

Section: The Adenosine Modulation System – Dynamics Of Its Extracellumentioning

confidence: 99%

“…Currently, there is simply no information about which nucleoside transporters or which ecto-nucleotidases are present in these different cell types and subcellular compartments in the brain parenchyma, a critical piece of information to begin understanding the dynamics of extracellular adenosine levels associated with each of the different signaling roles fulfilled by adenosine. In fact, as occurs for extracellular ATP, extracellular adenosine can also play multiple physiological roles in the brain parenchyma: (i) as a synaptic neuromodulator contributing to sharp information salience in neuronal circuits , which is probably the better established role for adenosine in the brain; (ii) as an astrocytic modulator, controlling metabolism (H aberg et al 2000;Blood et al 2003;Lemos et al 2015;Duarte et al 2016), calcium waves (Kawamura and Kawamura 2011;Kanno and Nishizaki 2012) and the ability of astrocytes to uptake neurotransmitters (Nishizaki et al 2002;Matos et al 2012a,b;Crist ovão-Ferreira et al 2013); (iii) as an astrocyte to neuron signal, linking astrocytic activation to heterosynaptic depression (Manzoni et al 1994;Serrano et al 2006;Andersson et al 2007); (iv) as a controller of oligodendrocyte differentiation and functions (Rivkees and Wendler 2011;Coppi et al 2015); (v) as a microglia modulator, controlling the proliferation (Haselkorn et al 2010;Gomes et al 2013;George et al 2015), motility (Orr et al 2009;Choi et al 2011;Ohsawa et al 2012) and reactivity of microglia (Saura et al 2005;van et al 2009;Dai et al 2010a;Rebola et al 2011;Madeira et al 2015;Newell et al 2015); (vi) as a microglia to neuron signal, controlling short-term synaptic plasticity upon microglia activation (Lauro et al 2010;George et al 2016); (vii) as an endothelial modulator, controlling the vasodilation of brain capillaries…”

Section: Signaling By Adenosinementioning

confidence: 99%

How does adenosine control neuronal dysfunction and neurodegeneration?

Cunha

2016

Journal of Neurochemistry

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378

385

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The adenosine modulation system mostly operates through inhibitory A 1 (A 1 R) and facilitatory A 2A receptors (A 2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A 1 R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: highfrequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A 2A R; A 2A R switch off A 1 R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A 1 R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A 1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A 2A R, probably to bolster adaptive changes, but this heightens brain damage since A 2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A 2A R, whereas astrocytic and microglia A 2A R might control the spread of damage. The A 2A R signaling mechanisms are largely unknown since A 2A R are pleiotropic, coupling to different G proteins and non-canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A 1 R preconditioning and preventing excessive A 2A R function might afford maximal neuroprotection. Keywords: A 1 receptor, A 2A receptor, astrocyte, microglia, synaptic plasticity, synaptotoxicity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Relevance of modulation systems to tune information flow in brain circuitsThe goal of understanding the flow of information in neuronal circuits has traditionally been centered in studying the key processes sustaining synaptic transmission and plasticity -i.e. the role of glutamate and glutamate receptors, as well as to a lesser extent the role of GABA and its receptors. If one considers an analogy to the experience of watching TV, this corresponds to studying how the ON/OFF button impacts all Received April 4, 2016; revised manuscript received May 23, 2016; accepted June 23, 2016. Address correspondence and reprint requests to R. A. Cunha, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. E-mail: cunharod@gmail.com Abbreviations used: A 1 R, adenosine A 1 receptor; A 2A R, adenosine A 2A receptor; ADHD, attention deficit and hyperactivity disorder; BDNF, brain-derived neurotrophi...

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“…Experiments were carried out as before, with some modifications (Lemos et al 2012(Lemos et al ,2015.…”

Section: In Vitro Measurement Of Glucose Uptake In Accumbal Slicesmentioning

confidence: 99%

Hierarchical glucocorticoid-endocannabinoid interplay regulates the activation of the nucleus accumbens by insulin

Pinheiro

Lemos

Kaufmann

et al. 2016

Brain Research Bulletin

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Here we asked if insulin activation of the nucleus accumbens in vitro is reflected by an increase in (3)H-deoxyglucose ([(3)H]DG) uptake, thus subserving a new model to study molecular mechanisms of central insulin actions. Additionally, we investigated the dependence of this insulin effect on endocannabinoids and corticosteroids, two major culprits in insulin resistance. We found that in acute accumbal slices, insulin (3 and 300nM but not at 0.3nM) produced an increase in [(3)H]DG uptake. The synthetic cannabinoid agonist, WIN55212-2 (500nM) and the glucocorticoid dexamethasone (10μM), impaired insulin (300nM) action on [(3)H]DG uptake. The glucocorticoid receptor (GcR) antagonist, mifepristone (10μM) prevented dexamethasone from inhibiting insulin's action. Strikingly, this anti-insulin action of dexamethasone was also blocked by two CB1 cannabinoid receptor (CB1R) antagonists, O-2050 (500nM) and SR141716A (500nM), as well as by tetrahydrolipstatin (10μM), an inhibitor of diacylglycerol lipases-the enzymes responsible for the synthesis of the endocannabinoid, 2-arachidonoyl-glycerol (2-AG). On the other hand, the blockade of the post-synaptic 2-AG metabolizing enzymes, α,β-serine hydrolase domain 6/12 by WWL70 (1μM) also prevented the action of insulin, probably via increasing endogenous 2-AG tone. Additionally, an anti-insulin receptor (InsR) antibody immunoprecipitated CB1Rs from accumbal homogenates, indicating a physical complexing of CB1Rs with InsRs that supports their functional interaction. Altogether, insulin stimulates glucose uptake in the nucleus accumbens. Accumbal GcR activation triggers the synthesis of 2-AG that in turn binds to the known CB1R-InsR heteromer, thus impeding insulin signaling.

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Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain

Cited by 21 publications

References 47 publications

AMP‐activated protein kinase (AMPK) activator A‐769662 increases intracellular calcium and ATP release from astrocytes in an AMPK‐independent manner

AMP‐activated protein kinase (AMPK) activator A‐769662 increases intracellular calcium and ATP release from astrocytes in an AMPK‐independent manner

How does adenosine control neuronal dysfunction and neurodegeneration?

Hierarchical glucocorticoid-endocannabinoid interplay regulates the activation of the nucleus accumbens by insulin

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