Desensitization and internalization of adenosine A1 receptors in rat brain by in vivo treatment with R-PIA: involvement of coated vesicles

Ruiz, María Ángeles; Sanz, Juana María; González-Calero, Gloria; Fernández, Marta Cendón; Andrés, Antonio; Cubero, Ana; Ros, Manuel

doi:10.1016/0167-4889(95)00152-2

Cited by 48 publications

(32 citation statements)

References 30 publications

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“…This has been verified with A 1 receptors, which are down-regulated and desensitized after adenosine or analogue exposure in in vitro (Abbracchio et al 1992;Hettinger et al 1998;Vendite et al 1998) and in vivo systems Ruiz et al 1996). In agreement, acute activation of A 1 receptors is neuroprotective, reducing damage to neurons, whereas A 1 receptor blockade potentiates damage (Fredholm 1997;von Lubitz 1999;de Mendonça et al 2000).…”

supporting

confidence: 51%

Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

Castillo

León

Ruiz

et al. 2008

Journal of Neurochemistry

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During hypoxia, extracellular adenosine levels are increased to prevent cell damage, playing a neuroprotective role mainly through adenosine A 1 receptors. The aim of the present study was to analyze the effect of hypoxia in both adenosine A 1 and A 2A receptors endogenously expressed in C6 glioma cells. Two hours of hypoxia (5% O 2 ) caused a significant decrease in adenosine A 1 receptors. The same effect was observed at 6 h and 24 h of hypoxia. However, adenosine A 2A receptors were significantly increased at the same times. These effects were not due to hypoxia-induced alterations in cells number or viability. Changes in receptor density were not associated with variations in the rate of gene expression. Furthermore, hypoxia did not alter HIF-1a expression in C6 cells. However, HIF-3a, CREB and CREM were decreased. Adenosine A 1 and A 2A receptor density in normoxic C6 cells treated with adenosine for 2, 6 and 24 h was similar to that observed in cells after oxygen deprivation. When C6 cells were subjected to hypoxia in the presence of adenosine deaminase, the density of receptors was not significantly modulated. Moreover, DPCPX, an A 1 receptor antagonist, blocked the effects of hypoxia on these receptors, while ZM241385, an A 2A receptor antagonist, was unable to prevent these changes. These results suggest that moderate hypoxia modulates adenosine receptors and cAMP response elements in glial cells, through a mechanism in which endogenous adenosine and tonic A 1 receptor activation is involved.

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supporting

confidence: 51%

Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

Castillo

León

Ruiz

et al. 2008

Journal of Neurochemistry

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“…Accordingly, upregulation of adenosine A 1 receptor expression has been observed in mice and rats after chemically induced seizures and in post-mortem tissue of humans suffering from epilepsy Vanore et al, 2001;Angelatou et al, 1991). An upregulation of adenosine A 1 receptors in the presence of extracellular adenosine at high concentrations (as it occurs during seizures) seems a rather unusual feature, since adenosine A 1 receptors are normally desensitized in the presence of high concentrations of adenosine or after a prolonged exposure to selective agonists (Abbracchio et al, 1992;Ruiz et al, 1996;Hettinger et al, 1998;Latini and Pedata, 2001). The data presented here might provide an explanation for this paradoxical situation, since IL-6-induced synthesis of A 1 receptors could counteract or overrule A 1 receptor desensitization caused by prolonged exposure to high levels of adenosine released during seizures.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Biber

Pinto-Duarte

Wittendorp

et al. 2007

Neuropsychopharmacol

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The immunological response in the brain is crucial to overcome neuropathological events. Some inflammatory mediators, such as the immunoregulatory cytokine interleukin-6 (IL-6) affect neuromodulation and may also play protective roles against various noxious conditions. However, the fundamental mechanisms underlying the long-term effects of IL-6 in the brain remain unclear. We now report that IL-6 increases the expression and function of the neuronal adenosine A 1 receptor, with relevant consequences to synaptic transmission and neuroprotection. IL-6-induced amplification of A 1 receptor function enhances the responses to readily released adenosine during hypoxia, enables neuronal rescue from glutamate-induced death, and protects animals from chemically induced convulsing seizures. Taken together, these results suggest that IL-6 minimizes the consequences of excitotoxic episodes on brain function through the enhancement of endogenous adenosinergic signaling.

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“…In fact, several works suggest that neuronal A 1 R desensitization occurs in large time frames (12Y24 h) of exposure to exogenously added A 1 R agonists in vitro (e.g., [184,186,187]) as well as in vivo (e.g., [188,189]). The time course of desensitization of A 1 Rs is particularly critical to understand if adenosine maintains its neuroprotective efficiency in chronic noxious brain situations.…”

Section: Modification Of Adenosine Metabolism On Stressful Conditionsmentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

483

432

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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Desensitization and internalization of adenosine A1 receptors in rat brain by in vivo treatment with R-PIA: involvement of coated vesicles

Cited by 48 publications

References 30 publications

Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

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Desensitization and internalization of adenosine A1 receptors in rat brain by in vivo treatment with R-PIA: involvement of coated vesicles

Cited by 48 publications

References 30 publications

Modulation of adenosine A1 and A2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

Modulation of adenosine A1 and A2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

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Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine