AICA riboside both activates AMP‐activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus

Gadalla, Anne E.; Pearson, Tim; Currie, Ailsa J.; Dale, Nicholas; Hawley, Simon A.; Sheehan, Mike; Hirst, Warren D.; Michel, Anton D.; Randall, Andrew D.; Hardie, D. Grahame; Frenguelli, Bruno G.

doi:10.1046/j.1471-4159.2003.02253.x

Cited by 136 publications

(124 citation statements)

References 52 publications

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“…AICAR enters the cell through the adenosine transporter [21]. Intracellular phosphorylation by adenosine kinase results in its AMPK activating form, "ZMP" [45].…”

Section: Resultsmentioning

confidence: 99%

“…Intracellular phosphorylation by adenosine kinase results in its AMPK activating form, "ZMP" [45]. In rat brain slices, AICAR treatment induced depression of excitatory synaptic transmission in CA1 hippocampus [21]. This effect of AICAR was due to indirect activation of adenosine receptors because AICAR competes with adenosine for access to the transporter, increasing extracellular adenosine [21].…”

Section: Resultsmentioning

confidence: 99%

“…In rat brain slices, AICAR treatment induced depression of excitatory synaptic transmission in CA1 hippocampus [21]. This effect of AICAR was due to indirect activation of adenosine receptors because AICAR competes with adenosine for access to the transporter, increasing extracellular adenosine [21]. Treating astrocytes with adenosine, and its derivatives AMP, ADP, and ATP, induces stellation by P1 purinoceptor activation [3].…”

Section: Resultsmentioning

confidence: 99%

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A pharmacological activator of AMP-activated protein kinase (AMPK) induces astrocyte stellation

Favero

Mandell

2007

Brain Research

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AMP-activated protein kinase (AMPK) represents a key energy-sensing molecule in many cell types. Because astrocytes are key mediators of metabolic signaling in the brain, we have initiated studies on the expression and activation of AMPK in these cells. Treatment of cultured rat cortical astrocytes with a pharmacological AMPK activator, AICA-riboside (AICAR) resulted in a time-and concentration-dependent increase in phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a direct substrate. AICAR treatment also induced a transition from epithelioid to stellate morphology in a time-and concentration-dependent manner. As stellation is indicative of actin cytoskeletal reorganization, the formation of stress fibers and focal adhesions in response to AICAR was assessed. AICAR-induced stellation correlated with F-actin disassembly and focal adhesion dispersal. Furthermore, transient transfection of an activated RhoA construct prevented AICAR-induced stellation, indicating a mechanism upstream of RhoA. Use of pharmacological inhibitor compound C prevented AICAR-induced stellation demonstrating necessity of AMPK activity for the response. Our findings suggest that AMPK mediates morphological alterations of astrocytes in response to energy depletion.

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“…AICAR enters the cell through the adenosine transporter [21]. Intracellular phosphorylation by adenosine kinase results in its AMPK activating form, "ZMP" [45].…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A pharmacological activator of AMP-activated protein kinase (AMPK) induces astrocyte stellation

Favero

Mandell

2007

Brain Research

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“…These nucleoside transporters are responsible for transporting nucleosides such as adenosine and uridine into the cell. In the brain, AICAR elevates adenosine levels, thought to be mediated by competition for or blockade of ENT1 27. Therefore, we used a highly selective inhibitor of ENT1, NBMPR, to demonstrate that ENT1 inhibition is sufficient to block the effect of AICAR on HGP and AMPK signalling.…”

Section: Discussionmentioning

confidence: 99%

Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

Logie

Lees

Allwood

et al. 2018

Diabetes Obesity Metabolism

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AimRecently we have observed differences in the ability of metformin and AICAR to repress glucose production from hepatocytes using 8CPT‐cAMP. Previous results indicate that, in addition to activating protein kinase A, 8CPT‐modified cAMP analogues suppress the nitrobenzylthioinosine (NBMPR)‐sensitive equilibrative nucleoside transporter ENT1. We aimed to exploit 8CPT‐cAMP, 8CPT‐2‐Methyl‐O‐cAMP and NBMPR, which is highly selective for a high‐affinity binding‐site on ENT1, to investigate the role of ENT1 in the liver‐specific glucose‐lowering properties of AICAR and metformin.MethodsPrimary mouse hepatocytes were incubated with AICAR and metformin in combination with cAMP analogues, glucagon, forskolin and NBMPR. Hepatocyte glucose production (HGP) and AMPK signalling were measured, and a uridine uptake assay with supporting LC‐MS was used to investigate nucleoside depletion from medium by cells.ResultsAICAR and metformin increased AMPK pathway phosphorylation and decreased HGP induced by dibutyryl cAMP and glucagon. HGP was also induced by 8CPT‐cAMP, 8CPT‐2‐Methyl‐O‐cAMP and NBMPR; however, in each case this was resistant to suppression by AICAR but not by metformin. Cross‐validation of tracer and mass spectrometry studies indicates that 8CPT‐cAMP, 8CPT‐2‐Methyl‐O‐cAMP and NBMPR inhibited the effects of AICAR, at least in part, by impeding its uptake into hepatocytes.ConclusionsWe report for the first time that suppression of ENT1 induces HGP. ENT1 inhibition also impedes uptake and the effects of AICAR, but not metformin, on HGP. Further investigation of nucleoside transport may illuminate a better understanding of how metformin and AICAR each regulate HGP.

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“…In these experiments, sensors were invaluable as they allowed the kinetics of enhanced adenosine release to be established, which would not have been possible through the use of receptor antagonists. Furthermore, they permitted the effects of inhibition of ecto-ATPases and ENTs on adenosine release to be established directly since the commonly used surrogate for adenosine release, the depression of excitatory synaptic transmission, is inhibited nonspecifically by POM1 [71], ARL 67156 [72] and by ENT inhibition [67,73]. Given that both D-ribose and adenine have been used safely in humans, these studies offer the possibility that RibAde treatment may be of value in a range of neurological conditions characterised by reductions in tissue ATP, as D-ribose has been for the energetically compromised heart, in vivo and in humans [74].…”

Section: Purine Salvagementioning

confidence: 99%

Measurement of purine release with microelectrode biosensors

Dale

Frenguelli

2011

Purinergic Signalling

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Purinergic signalling departs from traditional paradigms of neurotransmission in the variety of release mechanisms and routes of production of extracellular ATP and adenosine. Direct real-time measurements of these purinergic agents have been of great value in understanding the functional roles of this signalling system in a number of diverse contexts. Here, we review the methods for measuring purine release, introduce the concept of microelectrode biosensors for ATP and adenosine and explain how these have been used to provide new mechanistic insight in respiratory chemoreception, synaptic physiology, eye development and purine salvage. We finish by considering the association of purine release with pathological conditions and examine the possibilities that biosensors for purines may one day be a standard part of the clinical diagnostic tool chest.Keywords Biosensor . Real-time measurement . Epilepsy . Stroke . Chemosensory mechanisms . DevelopmentThe need for real-time purine measurementThe traditional paradigm of synaptic transmission involves exocytotic release of transmitter from a defined presynaptic structure into the narrow gap of the synaptic cleft where it diffuses to activate receptors on the closely apposed postsynaptic membrane. Release is time-locked to the presynaptic action potential and results in the predictable occurrence of postsynaptic events on defined time scales. While capturing the essence of synaptic transmission, this paradigm is an oversimplification. For example, transmitters such as GABA [1] and glutamate [2] can spill out of the synaptic cleft to have more diffuse and widespread actions than this classical model suggests. Under pathological conditions, transmitters and neurotransmitters, such as glutamate [3], can be released by the reversal of Na + -dependent concentrative transporters.The purines, ATP and adenosine, depart from this paradigm even more comprehensively. ATP can indeed be released at synapses [4,5]. However, in the CNS, it seems that it acts mainly as a cotransmitter [6,7], and there are very few synapses where it acts as the principal transmitter. ATP is also released by glial cells [8,9] for the most part via exocytosis [10,11] but see [12]. However, ATP can also be released via a variety of channel-mediated mechanisms (for example, via gap junction hemichannels [13][14][15] and volume-activated channels [16,17]). Receptors for ATP are widespread throughout the CNS; yet, the cellular sources of ATP release to activate these receptors are not immediately obvious. In addition, although ATP can be broken down to ADP and further to adenosine, these breakdown products are themselves active at particular receptor subtypes.The routes for adenosine release and the cellular sources seem to be even more mysterious than those for ATP. For example, there is abundant evidence that adenosine can arise from the breakdown of previously released ATP [18].

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AICA riboside both activates AMP‐activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus

Cited by 136 publications

References 52 publications

A pharmacological activator of AMP-activated protein kinase (AMPK) induces astrocyte stellation

A pharmacological activator of AMP-activated protein kinase (AMPK) induces astrocyte stellation

Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

Measurement of purine release with microelectrode biosensors

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