Altered surface expression of P2Y receptor with narcolepsy-associated mutations.

Narcolepsy with cataplexy is a neurological sleep disorder, which is believed to arise from the autoimmune destruction of hypocretin-producing neurons. The purinergic receptor P2Y is associated with narcolepsy in genome-wide association studies, and P2RY11 sequencing has further revealed eight rare missense mutations associated with the disease. Some of these mutations alter the signaling properties of P2Y, but for some, no functional effects have been discovered so far.
This study examined the surface expression of the eight narcolepsy-associated P2Y mutations using an in vitro surface expression assay.
The assay showed excellent discrimination between cells transfected with tagged wild type and the untagged P2Y receptor, proving complete specificity towards the 3HA-N-tag used for the assay. Our results show a decreased surface expression of the R307W P2Y mutant and a surface expression similar to wild type for the other seven mutants.
Based on the present findings, alteration in surface expression is not likely to play a role in how P2Y influences narcolepsy pathogenesis. This is important because intact surface expression increases the usefulness of P2Y as a future drug target.