Conn P Michael, Knollman Paul E, Brothers Shaun P, Janovick Jo Ann
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA.
Mol Endocrinol. 2006 Dec;20(12):3035-41. doi: 10.1210/me.2006-0066. Epub 2006 Mar 23.
Recent studies reveal that a number of G protein-coupled receptors (GPCRs) and other proteins are expressed inefficiently at the site normally associated with their biological action. In the case of some GPCRs, large amounts of receptor (perhaps more than half) may be destroyed without ever binding ligand or even arriving at the plasma membrane. For the human GnRH receptor (GnRHR), this apparent inefficiency has evolved under strong and convergent evolutionary pressure. The result is a human GnRHR molecule that is delicately balanced between either expression at the plasma membrane (PM) or retention/degradation in the endoplasmic reticulum, an effect mediated by engagement with the cellular quality control system. This balance appears to be the reason that the human receptor, but not the rat or mouse counterpart (which are more robustly routed to the PM), is highly susceptible to single-point mutations that result in disease. A single change in net charge is sufficient to tip the balance in favor of the endoplasmic reticulum and diminish GnRHR available at the PM. The apparent paradox that results from observing convergent pressure for evolution of a receptor that is both inefficiently produced and highly susceptible to mutational disease suggests that this approach must offer a strong advantage. This review focuses on the evolved mechanisms and considers that this is an underappreciated mechanism by which the cell controls functional levels of receptors and other proteins at the posttranslational level.
最近的研究表明，许多G蛋白偶联受体（GPCRs）和其他蛋白质在通常与其生物学作用相关的部位表达效率低下。就某些GPCRs而言，大量的受体（可能超过一半）可能在未结合配体甚至未到达质膜之前就被破坏了。对于人类促性腺激素释放激素受体（GnRHR）来说，这种明显的低效率是在强大且趋同的进化压力下演变而来的。结果是，人类GnRHR分子在内质网中的保留/降解与在质膜（PM）上的表达之间微妙地平衡，这种平衡是通过与细胞质量控制系统的相互作用介导的。这种平衡似乎就是为什么人类受体（而非大鼠或小鼠的对应受体，后者更稳定地被转运到质膜）对导致疾病的单点突变高度敏感的原因。净电荷的单一变化就足以使平衡倾向于内质网，减少质膜上可用的GnRHR。观察到一种既产生效率低下又对突变疾病高度敏感的受体在进化上存在趋同压力，这一明显的矛盾表明这种方式必定具有强大的优势。本综述聚焦于进化出的机制，并认为这是一种未得到充分认识的机制，通过该机制细胞在翻译后水平控制受体和其他蛋白质的功能水平。
