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 Lys191 which destabilizes a Cys14-Cys200 bridge required by the cellular quality control system (QCS). A 4-amino, non-contiguous “motif” (Leu112, Gln208, Leu300, Asp302) is required for this effect. The hGnRHR sequence, with or without Lys191, 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 Lys191 is deleted from hGnRHR and co-expressed with calnexin, IP production is similar to the rat sequence. When rat GnRHR containing Lys191 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.