TY - JOUR
T1 - Altered surface expression of P2Y11 receptor with narcolepsy-associated mutations
AU - Dommer, Maja Wallentin
AU - Dreisig, Karin
AU - Kornum, Birgitte Rahbek
PY - 2019
Y1 - 2019
N2 - Background: Narcolepsy with cataplexy is a neurological sleep disorder, which is believed to arise from the autoimmune destruction of hypocretin-producing neurons. The purinergic receptor P2Y11 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 P2Y11, but for some, no functional effects have been discovered so far. Methods: This study examined the surface expression of the eight narcolepsy-associated P2Y11 mutations using an in vitro surface expression assay. Results: The assay showed excellent discrimination between cells transfected with tagged wild type and the untagged P2Y11 receptor, proving complete specificity towards the 3HA-N-tag used for the assay. Our results show a decreased surface expression of the R307W P2Y11 mutant and a surface expression similar to wild type for the other seven mutants. Conclusion: Based on the present findings, alteration in surface expression is not likely to play a role in how P2Y11 influences narcolepsy pathogenesis. This is important because intact surface expression increases the usefulness of P2Y11 as a future drug target.
AB - Background: Narcolepsy with cataplexy is a neurological sleep disorder, which is believed to arise from the autoimmune destruction of hypocretin-producing neurons. The purinergic receptor P2Y11 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 P2Y11, but for some, no functional effects have been discovered so far. Methods: This study examined the surface expression of the eight narcolepsy-associated P2Y11 mutations using an in vitro surface expression assay. Results: The assay showed excellent discrimination between cells transfected with tagged wild type and the untagged P2Y11 receptor, proving complete specificity towards the 3HA-N-tag used for the assay. Our results show a decreased surface expression of the R307W P2Y11 mutant and a surface expression similar to wild type for the other seven mutants. Conclusion: Based on the present findings, alteration in surface expression is not likely to play a role in how P2Y11 influences narcolepsy pathogenesis. This is important because intact surface expression increases the usefulness of P2Y11 as a future drug target.
KW - Mutagenesis
KW - Narcolepsy
KW - P2Y
KW - Surface expression assay
U2 - 10.1016/j.pharep.2019.05.005
DO - 10.1016/j.pharep.2019.05.005
M3 - Journal article
C2 - 31450027
AN - SCOPUS:85071028175
SN - 1734-1140
VL - 71
SP - 926
EP - 928
JO - Pharmacological Reports
JF - Pharmacological Reports
IS - 5
ER -