Impaired receptor binding and activation associated with a human prostacyclin receptor polymorphism.

摘要: Abstract The human prostacyclin receptor (hIP) is a seven transmembrane-spanning G-protein-coupled that plays an important role in vascular homeostasis. Recent genetic analyses (SNP database, NCBI) have revealed the first two polymorphisms within coding sequence, V25M and R212H. Here we present structure-function characterizations of these at physiological pH (7.4) acidic (6.8) would be encountered during stress such as renal, respiratory, or heart failure. Through series competition binding G-protein activation assays (measured by cAMP production), determined polymorph exhibited agonist similar to wild-type normal (7.4). However, R212H variant demonstrated significant decrease affinity lower (R212H 7.4,K i = 2.2 ± 1.2 nm; 6.8K 45.6 12.0 nm). also abnormal both 7.4 6.8 (pH 7.4, EC50 2.8 0.5 nm versus hIP 0.1 6.8, 3.2 1.6 0.2 Polymorphisms potentially may predictors disease progress biological stressors acidosis which urgent correction bodily required restore hemostasis vasodilation. This study provides mechanistic basis for further research into risk factors pharmacogenetics cardiovascular associated with hIP.