Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA.
Traffic. 2009 May;10(5):552-66. doi: 10.1111/j.1600-0854.2009.00890.x. Epub 2009 Feb 11.
The intrinsic structural determinants for export trafficking of G protein-coupled receptors (GPCRs) have been mainly identified in the termini of the receptors. In this report, we determined the role of the first intracellular loop (ICL1) in the transport from the endoplasmic reticulum (ER) to the cell surface of GPCRs. The alpha(2B)-adrenergic receptor (AR) mutant lacking the ICL1 is unable to traffic to the cell surface and to initiate signaling measured as ERK1/2 activation. Mutagenesis studies identify a single Leu48 residue in the ICL1 modulates alpha(2B)-AR export from the ER. The ER export function of the Leu48 residue can be substituted by Phe, but not Ile, Val, Tyr and Trp, and is unlikely involved in correct folding or dimerization of alpha(2B)-AR in the ER. Importantly, the isolated Leu residue is remarkably conserved in the center of the ICL1s among the family A GPCRs and is also required for the export to the cell surface of beta(2)-AR, alpha(1B)-AR and angiotensin II type 1 receptor. These data indicate a crucial role for a single Leu residue within the ICL1 in ER export of GPCRs.
G 蛋白偶联受体（GPCRs）的固有结构决定因素主要在受体的末端被确定。在本报告中，我们确定了第一个细胞内环（ICL1）在 GPCR 从内质网（ER）到细胞表面的运输中的作用。缺乏 ICL1 的 alpha(2B)-肾上腺素能受体（AR）突变体无法转运到细胞表面并引发 ERK1/2 激活等信号转导。突变研究确定 ICL1 中的单个亮氨酸 48 残基调节 alpha(2B)-AR 从 ER 输出。亮氨酸 48 残基的 ER 输出功能可以被苯丙氨酸取代，但不能被异亮氨酸、缬氨酸、酪氨酸和色氨酸取代，并且不太可能参与 alpha(2B)-AR 在 ER 中的正确折叠或二聚化。重要的是，在家族 A GPCR 中，ICL1 中心的孤立亮氨酸残基非常保守，并且对于 beta(2)-AR、alpha(1B)-AR 和血管紧张素 II 型 1 受体的细胞表面输出也是必需的。这些数据表明 ICL1 内的单个亮氨酸残基在 GPCR 的 ER 输出中起着关键作用。
