The hydrophobic amino acid residues in the membrane‐proximal C tail of the G protein‐coupled vasopressin V2 receptor are necessary for transport‐competent receptor folding

It is believed that the membrane‐proximal C tail of the G protein‐coupled receptors forms an additional alpha helix with amphipathic properties (helix 8). It was previously shown for the vasopressin V2 receptor (V2R) that a conserved dileucine motif (L 339 , L 340 ) in this putative helix 8 is necessary for endoplasmic reticulum (ER) to Golgi transfer of the receptor. Here, we demonstrate that the other hydrophobic residues forming the non‐polar side of this helix (F 328 , V 332 and L 336 ) are also transport‐relevant. In contrast, the multiple serine residues contributing to the more hydrophilic side (S 330 , S 331 , S 333 , S 334 , S 338 ) do not influence receptor trafficking. In addition, we show unambiguously by the use of pharmacological chaperones that the hydrophobic residues of the putative helix 8 do not form a transport signal necessary for receptor sorting into ER to Golgi vesicles. Instead, they are necessary to establish a transport‐competent folding state in the early secretory pathway.