Investigation of the effect of the farnesyl protein transferase inhibitor R115777 on isoprenylation and intracellular signalling by the prostacyclin receptor

British Journal of Pharmacology
Sarah J O'Meara, B Therese Kinsella

Abstract

The human (h) and mouse (m) prostacyclin receptors (IPs) undergo isoprenylation through attachment of a C-15 farnesyl moiety within their conserved carboxyl terminal -CSLC sequences. Herein, the effects of a novel farnesyl transferase inhibitor R115777 on signalling by the hIP and mIP, overexpressed in human embryonic kidney 293 cells, and by the hIP endogenously expressed in human erythroleukaemia cells were investigated. R115777 significantly impaired IP-mediated cyclic AMP generation (IC(50) 0.37-0.60 nm) and intracellular calcium ([Ca(2+)](i)) mobilization (IC(50) 37-65 nm), but had no effect on signalling by the control nonisoprenylated beta(2) adrenergic receptor or the alpha or beta isoforms of the human thromboxane A(2) receptor (TP). Additionally, R115777 significantly reduced IP-mediated cross-desensitization of signalling by the TP alpha, but not by the TP beta, isoform of the human TP and impaired the farnesylation-dependent processing of the chaperone HDJ-2 protein (IC(50) 4.5 nm). Furthermore, R115777 fully impaired isoprenylation of both the Ha-Ras(WT) and Ha-Ras(CSLC) in vitro and in whole cells confirming that, unlike N-Ras and Ki-Ras, the -CSLC motif associated with the IP cannot support alternative geranylger...Continue Reading

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Citations

Nov 20, 2012·Arteriosclerosis, Thrombosis, and Vascular Biology·Salam IbrahimEmer M Smyth
Mar 10, 2011·British Journal of Pharmacology·K T SanthoshS Dakshinamurti
Feb 5, 2014·British Journal of Pharmacology·K T SanthoshS Dakshinamurti
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Dec 15, 2005·The Journal of Pharmacology and Experimental Therapeutics·Xiaohua XueAnne Fourie
Feb 25, 2017·British Journal of Pharmacology

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