title: 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.
authors.affiliation: Department of Physiology and Biophysics, Genetics, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Yunjia
authors.initials: Y
authors.lastname: Chen
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Christopher
authors.initials: C
authors.lastname: Cottingham
authors.forename: Lori
authors.initials: L
authors.lastname: McMahon
authors.forename: Kai
authors.initials: K
authors.lastname: Jiao
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004569:Electroencephalography; D005452:Fluoresceins; D006624:Hippocampus / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009930:Organic Chemicals / Q000378:metabolism; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014970:Xanthines / Q000494:pharmacology / Q000627:therapeutic use; D000099273:Neurabins
chemical_list: D000241:Adenosine; D058916:Adenosine A1 Receptor Antagonists; D005452:Fluoresceins; D007608:Kainic Acid; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009930:Organic Chemicals; D010660:Phenylisopropyladenosine; D020710:RGS Proteins; D043682:Receptor, Adenosine A1; D013449:Sulfonamides; D014970:Xanthines; D000099273:Neurabins; C435731:fluoro jade; C523871:methyl N-((4-chlorophenyl)sulfonyl)-4-nitrobenzenesulfinimidoate; C098799:RGS4 protein; C051360:1,3-dipropyl-8-cyclopentylxanthine