1 Department of Psychiatry, University of Oxford, Warneford Hospital, UK.
2 Oxford Brookes University, Oxford, UK.
J Psychopharmacol. 2017 Dec;31(12):1519-1526. doi: 10.1177/0269881117715597. Epub 2017 Jun 28.
As well as being expressed as a full-length transcript, the group II metabotropic glutamate receptor 3 (GRM3, mGlu3) gene is expressed as an mRNA isoform which lacks exon 4 (GRM3Δ4) and which is predicted to encode a protein with a novel C terminus (called mGlu3Δ4). This variant may contribute to the mechanism by which GRM3 acts as a schizophrenia risk gene. However, little is known about the properties or function of mGlu3Δ4. Here, using transiently transfected HEK293T/17 cells, we confirm that GRM3Δ4 cDNA is translated, with mGlu3Δ4 existing as a homodimer as well as a monomer, and localizing primarily to cell membranes including the plasma membrane. Co-immunoprecipitation shows that mGlu3Δ4 interacts with canonical mGlu3. mGlu3Δ4 does not bind the mGlu2/3 antagonist [H]LY341495, but the presence of mGlu3Δ4 reduces binding of [H]LY341495 to mGlu3, paralleled by a decrease in the abundance of membrane-associated mGlu3. These experiments indicate that mGlu3Δ4 may negatively modulate mGlu3, and thereby impact on the roles of GRM3/mGlu3 in schizophrenia and as a therapeutic target.
除了全长转录本表达外，II 组代谢型谷氨酸受体 3（GRM3，mGlu3）基因还表达为一种缺失外显子 4 的 mRNA 异构体（GRM3Δ4），预计编码一种具有新型 C 末端的蛋白质（称为 mGlu3Δ4）。这种变体可能有助于解释 GRM3 作为精神分裂症风险基因的作用机制。然而，对于 mGlu3Δ4 的特性或功能知之甚少。在这里，我们使用瞬时转染的 HEK293T/17 细胞证实，GRM3Δ4 cDNA 可被翻译，mGlu3Δ4 以同源二聚体和单体的形式存在，主要定位于包括质膜在内的细胞膜上。免疫共沉淀显示 mGlu3Δ4 与经典的 mGlu3 相互作用。mGlu3Δ4 不结合 mGlu2/3 拮抗剂 [H]LY341495，但 mGlu3Δ4 的存在会降低 [H]LY341495 与 mGlu3 的结合，同时膜相关 mGlu3 的丰度也会减少。这些实验表明，mGlu3Δ4 可能负调节 mGlu3，从而影响 GRM3/mGlu3 在精神分裂症中的作用以及作为治疗靶点的作用。
