Species sequence differences determine the interaction of GnRH receptor with the cellular quality control system.

Plasma membrane expression (PME) of the human GnRHR (hGnRHR) is regulated by a primate-specific Lys(191) which destabilizes a Cys(14)-Cys(200) bridge required by the cellular quality control system (QCS). A 4-amino, non-contiguous "motif" (Leu(112), Gln(208), Leu(300), Asp(302)) is required for this effect. The hGnRHR sequence, with or without Lys(191), decreases PME and inositol phosphate (IP) production when co-expressed with calnexin, a QCS chaperone. WT rat GnRHR, decreases PME and IP production, when co-expressed with calnexin, but to a lesser degree than hGnRH. When the human sequence contains the rat motif, IP production is closer to that of rat GnRHR. When Lys(191) is deleted from hGnRHR and co-expressed with calnexin, IP production is similar to the rat sequence. When rat GnRHR containing Lys(191) and the human motif is co-expressed with calnexin, IP production is similar to cells expressing the hGnRHR. The motif sequence appears to be a determinant of calnexin recognition.