G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain.
G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain.
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DOI：
10.1016/1043-6618(95)86932-8
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发表时间：
1995-12
影响因子：
3.6
通讯作者：
M. Abbracchio;Roberta Brambilla;S. Ceruti;Hea Ok Kim;D. V. Lubitz;Kenneth A. Jacobson;Flaminio Cattabeni
中科院分区：
文献类型：
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作者：
M. Abbracchio;Roberta Brambilla;S. Ceruti;Hea Ok Kim;D. V. Lubitz;Kenneth A. Jacobson;Flaminio Cattabeni
最近克隆的 G 蛋白偶联腺苷 A3 受体被认为在脑缺血的病理生理学中发挥作用。由于磷脂酶 C 激活是脑缺血的早期反应，因此我们评估了 A3 选择性和非选择性腺苷类似物引发磷酸肌醇水解的能力。在肌[3H]肌醇标记的大鼠纹状体和海马切片中，A3激动剂以浓度依赖性方式刺激[3H]肌醇磷酸盐的形成。在纹状体中，效力顺序为 2-氯-N6-(3-碘苄基)-腺苷-5'-N-甲基糖醛酰胺 > 或=N6-(3-碘苄基)-腺苷-5'-N-甲基糖醛酰胺 > N-甲基-1,3-二正丁基黄嘌呤-7-β-D-呋喃核酰胺 > or=5'-N-乙基羧酰胺腺苷 > or=N6-2-(4-氨基苯基)-乙基腺苷 > N6-(对磺苯基)-腺苷 = 1,3-二丁基黄嘌呤-7-核苷，这与克隆大鼠 A3 受体结合研究中的效力顺序相同。鸟苷-5'-O-(2-硫代二磷酸) 消除了磷脂酶 C 活性的刺激，证实了 G 蛋白偶联受体的参与。纹状体中磷脂酶 C 的激活高于海马，这与 A3 受体密度一致。腺苷类似物对磷脂酶 C 活性的刺激仅被黄嘌呤衍生物适度拮抗，并且其浓度远高于阻断腺苷 A1、A2A 和 A2b 受体所需的浓度。在 A1/A2 拮抗剂存在的情况下，大鼠纹状体中选择性出现 A3。因此，刺激磷脂酶C活性激动剂仅微弱地抑制毛喉素刺激的腺苷酸环化酶活性，这代表了哺乳动物大脑中A3受体的主要转导机制，并且也许A3受体介导的缺血大脑中肌醇磷酸的增加通过提高细胞内钙水平而导致神经变性。
The recently cloned G protein-coupled adenosine A3 receptor has been proposed to play a role in the pathophysiology of cerebral ischemia. Because phospholipase C activation occurs as a very early response to brain ischemia, we evaluated the ability of A3- selective and nonselective adenosine analogues to elicit phosphoinositide hydrolysis. In myo-[3H]inositol-labeled rat striatal and hippocampal slices, A3 agonists stimulated formation of [3H]inositol phosphates in a concentration-dependent manner. In striatum, the potency order was 2-chloro-N6-(3-iodobenzyl)- adenosine-5'-N-methyluronamide > or=N6-(3-iodobenzyl)- adenosine-5'-N-methyluronamide > N-methyl-1,3-di-n-butylxanthine-7-beta-D-ribofuronamide > or=5'-N-ethylcarboxamidoadenosine > or=N6-2-(4-aminophenyl)-ethyladenosine > N6-(p-sulfophenyl)-adenosine = 1,3-dibutylxanthine-7- riboside, which is identical to the potency order in binding studies at cloned rat A3 receptors. Stimulation of phospholipase C activity was abolished by guanosine-5'-O-(2-thiodiphosphate), confirming the involvement of a G protein-coupled receptor. Activation of phospholipase C was higher in the striatum than in the hippocampus, consistent with A3 receptor densities. Stimulation of phospholipase C activity by adenosine analogues was only modestly antagonized by xanthine derivatives and at much higher concentrations than needed for blocking adenosine A1, A2A, and A2b receptors. In the presence of an A1/A2 antagonist, a selective A3 in rat striation. Thus, stimulation of phospholipase C activity agonist only weakly inhibited forskolin-stimulated adenylyl cyclase activity represents a principal transduction mechanism for A3 receptors in mammalian brain, and perhaps A3 receptor-mediated increases of inositol phosphates in the ischemic brain contribute to neurodegeneration by raising intracellular calcium levels.