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Allosteric modulation of adenosine A 1 receptor coupling to G‐proteins in brain
Author(s) -
Childers Steven R.,
Li Xinhui,
Xiao Ruoyu,
Eisenach James C.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03044.x
Subject(s) - allosteric regulation , modulation (music) , coupling (piping) , neuroscience , chemistry , adenosine , biophysics , receptor , microbiology and biotechnology , biochemistry , biology , physics , materials science , acoustics , metallurgy
2‐Amino‐4,5,6,7‐tetrahydrobenzo(β)thiophen‐3‐yl 4‐chlorophenylmethanone (T62) is a member of a group of allosteric modulators of adenosine A 1 receptors tested in animal models of neuropathic pain to increase the efficacy of adenosine. To determine its mechanisms at the level of receptor‐G‐protein activation, the present studies examined the effect of T62 on A 1 ‐stimulated [ 35 S]guanosine‐5′‐O‐(γ‐thio)‐triphosphate ([ 35 S]GTPγS) binding in brain membranes, and by [ 35 S]GTPγS autoradiography using the A 1 agonist, phenylisopropyladenosine (PIA), to activate G‐proteins. In hippocampal membranes, T62 increased both basal and PIA‐stimulated [ 35 S]GTPγS binding. The effect of T62 was non‐competitive in nature, since it increased the maximal effect of PIA, with no effect on agonist potency. GTPγS saturation analysis showed that T62 increased the number of G‐proteins activated by agonist but had no effect on the affinity of activated G‐proteins for GTPγS. [ 35 S]GTPγS autoradiography showed that the neuroanatomical localization of T62‐stimulated [ 35 S]GTPγS binding was identical to that of PIA‐stimulated activity. The increase in PIA‐stimulated activity by T62 varied between brain regions, with areas of lower A 1 activation producing the largest percent modulation by T62. These results suggest a mechanism of allosteric modulators to increase the number of activated G‐proteins per receptor, and provide a neuroanatomical basis for understanding potential therapeutic effects of such drugs.