Sigma receptors negatively modulate agonist-stimulated phosphoinositide metabolism in rat brain.
Sigma receptors negatively modulate agonist-stimulated phosphoinositide metabolism in rat brain.
复制标题
Sigma 受体负向调节大鼠脑中激动剂刺激的磷酸肌醇代谢。
DOI：
10.1016/0014-2999(88)90678-4
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发表时间：
1988
影响因子：
5
通讯作者：
Rice,KC
中科院分区：
文献类型：
--
作者：
Bowen,WD;Kirschner,BN;Newman,AH;Rice,KC
研究了σ受体影响磷酸肌醇（PI）周转的能力。制备大鼠脑突触神经体，用[3 H]肌醇标记，并如Gusovsky和Daly（Neuropharmacol. 27：95，1988）。除（+）-3-PPP外，所有测试的σ配体在高于100 μ M的浓度下抑制磷酸肌醇（PI）周转的基础水平。100 μ M卡巴胆碱或去甲肾上腺素刺激IP产生的能力也被σ配体以剂量依赖性方式抑制。需要比影响基础活性低得多的浓度。阻断卡巴胆碱刺激的PI转换的效力的等级顺序为：（+）-喷他佐辛> 1，3-二-邻甲苯基胍=右啡烷>氟哌啶醇>左啡烷。效力的这种等级顺序与σ受体的亲和力（如在豚鼠脑中测定的）良好相关，r= 0.86。相关的（+）-阿片类药物和抗精神病药物缺乏对σ受体的亲和力，不能影响激动剂刺激的IP 1产生。有趣的是，（+）-3-PPP仅对卡巴胆碱效应产生部分抑制，表明该化合物在该系统中具有部分激动剂特性。sigma配体阻断激动剂刺激的PI转换的发现表明sigma受体是一个新受体家族的成员，该受体与细胞内机制偶联，该机制负调节磷酸肌醇信号系统的成分。因此，σ受体的激动剂可以调节其他递质的功效。
The ability of sigma receptors to affect phosphoinositide (PI) turnover was investigated. Rat brain synaptoneurosomes were prepared, labelled with [3H] myo-inositol, and assayed for production of [3H] linositol-1-phosphate (IP1) as described by Gusovsky and Daly (Neuropharmacol. 27: 95, 1988). All sigma ligands tested, with the exception of (+)-3-PPP, depressed the basal level of phosphoinositide (PI) turnover at concentrations above 100 uM. The ability of 100 uM carbachol or norepinephrine to stimulate IP production was also inhibited by sigma ligands in a dose-dependent manner. Much lower concentrations were required than to affect basal activity. The rank order of potency to block carbachol-stimulated PI turnover was:(+)-pentazocine> 1, 3-di-o-tolylguanidine= dextrallorphan> haloperidol> levallorphan. This rank order of potency correlated well with affinity at sigma receptors (as determined in guinea pig brain), r= 0.86. Related (+)-opiates and antipsychotic drugs which lack affinity for sigma receptors failed to affect agonist-stimulated IP1 production. Interestingly,(+)-3-PPP produced only partial inhibition of the carbachol effect, suggesting partial agonist properties of this compound in this system.The finding that sigma ligands block agonist-stimulated PI turnover suggests that sigma receptors are members of a novel family of receptors coupled to an intracellular mechanism (s) which negatively regulates components of the phosphoinositide signalling system. Agonists at sigma receptors may therefore modulate the efficacy of other transmitters.