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Neurabin scaffolding of adenosine receptor and RGS4 regulates anti-seizure effect of endogenous adenosine.

Abstract

Endogenous adenosine is an essential protective agent against neural damage by various insults to the brain. However, the therapeutic potential of adenosine receptor-directed ligands for neuroprotection is offset by side effects in peripheral tissues and organs. An increase in adenosine receptor responsiveness to endogenous adenosine would enhance neuroprotection while avoiding the confounding effects of exogenous ligands. Here we report novel regulation of adenosine-evoked responses by a neural tissue-specific protein, neurabin. Neurabin attenuated adenosine A(1) receptor (A1R) signaling by assembling a complex between the A1R and the regulator of G-protein signaling 4 (RGS4), a protein known to turn off G-protein signaling. Inactivation of the neurabin gene enhanced A1R signaling and promoted the protective effect of adenosine against excitotoxic seizure and neuronal death in mice. Furthermore, administration of a small molecule inhibitor of RGS4 significantly attenuated seizure severity in mice. Notably, the dose of kainate capable of inducing an ∼50% rate of death in wild-type (WT) mice did not affect neurabin-null mice or WT mice cotreated with an RGS4 inhibitor. The enhanced anti-seizure and neuroprotective effect achieved by disruption of the A1R/neurabin/RGS4 complex is elicited by the on-site and on-demand release of endogenous adenosine, and does not require administration of A1R ligands. These data identify neurabin-RGS4 as a novel tissue-selective regulatory mechanism for fine-tuning adenosine receptor function in the nervous system. Moreover, these findings implicate the A1R/neurabin/RGS4 complex as a valid therapeutic target for specifically manipulating the neuroprotective effects of endogenous adenosine.

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  • Authors

    Chen Y, Liu Y, Cottingham C, McMahon L, Jiao K, Greengard P, Wang Q

    Institution

    Department of Physiology and Biophysics, Genetics, University of Alabama, Birmingham, AL 35294, USA.

    Source

    The Journal of neuroscience : the official journal of the Society for Neuroscience 32:8 2012 Feb 22 pg 2683-95

    MeSH

    Adenosine
    Adenosine A1 Receptor Antagonists
    Animals
    Animals, Newborn
    Cell Death
    Cells, Cultured
    Cricetinae
    Cricetulus
    Disease Models, Animal
    Electroencephalography
    Hippocampus
    In Situ Nick-End Labeling
    Kainic Acid
    Male
    Mice
    Mice, Inbred C57BL
    Mice, Knockout
    Microfilament Proteins
    Models, Biological
    Nerve Tissue Proteins
    Organic Chemicals
    Phenylisopropyladenosine
    RGS Proteins
    Receptor, Adenosine A1
    Seizures
    Signal Transduction
    Sulfonamides
    Time Factors
    Transfection
    Xanthines

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22357852