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

VL - 71

SP - 926

EP - 928

JO - Pharmacological Reports

JF - Pharmacological Reports

SN - 1734-1140

IS - 5

ER -