Calnexin regulated gonadotropin-releasing hormone receptor plasma membrane expression
Calnexin regulated gonadotropin-releasing hormone receptor plasma membrane expression
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DOI：
10.1677/jme.1.02142
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发表时间：
2006-12-01
影响因子：
3.5
通讯作者：
Conn, P. Michael
中科院分区：
文献类型：
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作者：
Brothers, Shaun P.;Janovick, Jo Ann;Conn, P. Michael
相当大比例的人促性腺激素释放激素受体（GnRHR）通常留在内质网（ER）中；然而，几乎所有大鼠的GnRHR都被转运到质膜。当在任一受体中引入突变时，与野生型（WT）受体相比，质量控制系统（QCS）会将更多的蛋白质识别为错误折叠并滞留，导致在有激动剂存在时信号传导减少。钙连蛋白是QCS的一个组成部分，它降低了GnRHR在质膜上的表达，这种作用是由受体和钙连蛋白之间的物理相互作用介导的。只有人受体表现出信号传导减少，因为与人受体相比，大鼠GnRHR有更多的备用受体，使得钙连蛋白能够影响信号传导。当从人野生型GnRHR中缺失K - 191时，钙连蛋白不影响受体信号传导。去除这种氨基酸可减少受体错误折叠并增加质膜表达。大鼠野生型GnRHR中不存在K - 191。一种纠正GnRHR错误折叠的药理伴侣，在有钙连蛋白存在的情况下增加了人野生型GnRHR的表达。钙连蛋白显然保留错误折叠的GnRHR，但将正确折叠的受体转运到质膜。钙连蛋白的一个蛋白激酶C共有磷酸化位点发生突变促进了人GnRHR的滞留增加，这表明钙连蛋白的磷酸化控制着滞留机制。我们得出结论，一部分人和大鼠的野生型GnRHR似乎被钙连蛋白留在内质网中，这种作用降低了GnRHR的信号传导能力。
A significant proportion of human gonadotropin- releasing hormone receptors (GnRHRs) are normally retained in the endoplasmic reticulum (ER); however, nearly all rat GnRHRs are routed to the plasma membrane. When mutations are introduced into either receptor, considerably more of the proteins are recognized by the quality control system (QCS) as misfolded and retained compared with wild-type (WT) receptor, resulting in decreased signaling in the presence of agonist. Calnexin, a component of the QCS, decreased plasma membrane expression of the GnRHRs, an effect that was mediated by a physical interaction between the receptor and the calnexin. Only the human receptor showed reduced signaling because it had fewer spare receptors compared with the rat GnRHR, allowing calnexin to affect signaling. Calnexin did not affect receptor signaling when K-191 was deleted from the human WT GnRHR. Removal of this amino acid decreases receptor misfolding and increases plasma membrane expression. K-191 is not present in the rat WT GnRHR. A pharmacological chaperone that corrects GnRHR misfolding, increased expression of the human WT GnRHR in the presence of calnexin. Calnexin apparently retains misfolded GnRHRs but routes correctly folded receptors to the plasma membrane. Mutation of a calnexin protein kinase C consensus phosphorylation site promoted increased retention of the human GnRHR, suggesting that calnexin phosphorylation controls the retention mechanism. We conclude that a proportion of the human and the rat WT GnRHR appears to be retained in the ER by calnexin, an effect that decreases GnRHR signaling capacity.