Clusters of transmembrane residues are critical for human prostacyclin receptor activation

Biochemistry
Jeremiah StithamJohn Hwa

Abstract

Relaxation of vascular smooth muscle and prevention of blood coagulation are mediated by ligand-induced activation of the human prostacyclin (hIP) receptor, a seven-transmembrane-domain G-protein-coupled receptor (GPCR). In this study, we elucidate the molecular requirements for receptor activation within the region of the ligand-binding pocket, identifying transmembrane residues affecting potency. Eleven of 30 mutated residues in the region of the ligand-binding domain exhibited defective activation (decreased potency). These critical residues localized to four distinct clusters (analysis via a rhodopsin-based human prostacyclin receptor homology model). Residues Y75(2.65) (TMII), F95(3.28) (TMIII), and R279(7.40) (TMVII) comprised the immediate binding-pocket cluster and were shown to be essential for proper receptor activation, compared to equivalent expression levels of the wild-type hIP (WT EC(50) = 1.2 +/- 0.1 nM; Y75(2.65)A EC(50) = 347.3 +/- 62.8 nM, p < 0.001; F95(3.28)A EC(50) = 8.0 +/- 0.6 nM, p < 0.001; R279(7.40)A EC(50) = 130 +/- 63.0 nM, p < 0.001). Residues S20(1.39) (TMI), F24(1.43) (TMI), and F72(2.62) (TMII) were localized to a cluster involving P17(1.36), a critical residue thought to facilitate transmembran...Continue Reading

References

Sep 5, 2001·The Journal of Biological Chemistry·R S OstromP A Insel
Feb 21, 2002·The Journal of Biological Chemistry·Jeremiah StithamJohn Hwa
Dec 6, 2003·Pharmacological Reviews·Richard R NeubigUNKNOWN International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification

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Citations

Aug 19, 2007·Journal of the American Chemical Society·Youyong LiAbdelazize Laoui
Mar 17, 2007·American Journal of Respiratory Cell and Molecular Biology·Koichiro KamioStephen I Rennard
Mar 24, 2009·Journal of Molecular and Cellular Cardiology·Zsolt KaszaKathleen A Martin
Dec 14, 2006·Prostaglandins & Other Lipid Mediators·Kristina M FetalveroJohn Hwa
Dec 14, 2006·Prostaglandins & Other Lipid Mediators·Jeremiah StithamJohn Hwa
May 29, 2016·American Journal of Physiology. Heart and Circulatory Physiology·Yan Cheng NgSangho Kim
Jan 10, 2006·American Journal of Physiology. Heart and Circulatory Physiology·Kristina M FetalveroKathleen A Martin
Oct 4, 2006·The Journal of Biological Chemistry·Jeremiah StithamJohn Hwa
Feb 23, 2011·The Open Cardiovascular Medicine Journal·Aamer SandooGeorge D Kitas
Oct 27, 2015·Clinical Pharmacology and Therapeutics·M Holinstat, P F Bray

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