Hayes Dayna M, Braud Stephanie, Hurtado David E, McCallum Jennifer, Standley Steve, Isaac John T R, Roche Katherine W
Receptor Biology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Biochem Biophys Res Commun. 2003 Oct 10;310(1):8-13. doi: 10.1016/j.bbrc.2003.08.115.
Kainate receptors are a class of ionotropic glutamate receptors that are widely expressed in the mammalian brain, yet little is known about their physiological role or the mechanisms by which they are regulated. Kainate receptors are composed of multiple subunits (GluR5-7; KA1-2), which can combine to form homomeric or heteromeric channels. While the kainate receptor subunit KA2 can combine with GluR5-7 to form heteromeric channels, it does not form functional homomeric channels when expressed alone. In an attempt to identify the molecular mechanisms for this, we have characterized the trafficking and surface expression of KA2. We find that KA2 alone does not traffic to the plasma membrane and is retained in the endoplasmic reticulum (ER). In contrast, co-expression with GluR6 disrupts ER-retention of KA2 and allows plasma membrane expression. Using a chimeric reporter protein we have identified an ER-retention motif within the KA2 cytosolic domain. Recent studies have identified a consensus ER-retention motif (RRR) that is contained within both the NMDA receptor NR1 subunit and K(+) channels. While KA2 contains a similar stretch of amino acids within its C-terminus (RRRRR), unlike the NR1 motif, disruption of this motif with alternating glutamic acid residues does not disrupt ER-retention of KA2, suggesting a unique mechanism regulating KA2 surface expression.
海人藻酸受体是一类离子型谷氨酸受体，在哺乳动物大脑中广泛表达，但对于它们的生理作用或调节机制却知之甚少。海人藻酸受体由多个亚基（GluR5 - 7；KA1 - 2）组成，这些亚基可以组合形成同聚体或异聚体通道。虽然海人藻酸受体亚基KA2可以与GluR5 - 7组合形成异聚体通道，但单独表达时它不会形成功能性同聚体通道。为了确定其分子机制，我们对KA2的转运和表面表达进行了表征。我们发现单独的KA2不会转运到质膜，而是保留在内质网（ER）中。相比之下，与GluR6共表达会破坏KA2的内质网保留，并允许其在质膜表达。使用嵌合报告蛋白，我们在KA2胞质结构域中鉴定出一个内质网保留基序。最近的研究在NMDA受体NR1亚基和钾离子通道中都发现了一个共有内质网保留基序（RRR）。虽然KA2在其C末端含有一段类似的氨基酸序列（RRRRR），但与NR1基序不同的是，用交替的谷氨酸残基破坏这个基序并不会破坏KA2的内质网保留，这表明存在一种独特的机制来调节KA2的表面表达。
