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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Br+J+Pharmacol
2014 ; 171
(21
): 4797-807
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Investigating the molecular mechanisms through which FTY720-P causes persistent
S1P1 receptor internalization
#MMPMID24641481
Sykes DA
; Riddy DM
; Stamp C
; Bradley ME
; McGuiness N
; Sattikar A
; Guerini D
; Rodrigues I
; Glaenzel A
; Dowling MR
; Mullershausen F
; Charlton SJ
Br J Pharmacol
2014[Nov]; 171
(21
): 4797-807
PMID24641481
show ga
BACKGROUND AND PURPOSE: The molecular mechanism underlying the clinical efficacy
of FTY720-P is thought to involve persistent internalization and enhanced
degradation of the S1P1 receptor subtype (S1P1R). We have investigated whether
receptor binding kinetics and ?-arrestin recruitment could play a role in the
persistent internalization of the S1P1R by FTY720-P. EXPERIMENTAL APPROACH: [(3)
H]-FTY720-P and [(33) P]-S1P were used to label CHO-S1P1/3Rs for binding studies.
Ligand efficacy was assessed through [(35) S]-GTP?S binding and ?-arrestin
recruitment. Metabolic stability was evaluated using a bioassay measuring
intracellular Ca(2+) release. CHO-S1P1/3R numbers were determined, following
FTY720-P treatment using flow cytometry. KEY RESULTS: The kinetic off-rate of
[(3) H]-FTY720-P from the S1P1R was sixfold slower than from the S1P3R, and
comparable to [(33) P]-S1P dissociation from S1P1/3Rs. S1P and FTY720-P
stimulated [(35) S]-GTP?S incorporation to similar degrees, but FTY720-P was over
30-fold less potent at S1P3Rs. FTY720-P stimulated a higher level of ?-arrestin
recruitment at S1P1Rs, 132% of the total recruited by S1P. In contrast, FTY720-P
was a weak partial agonist at S1P3R, stimulating just 29% of the total ?-arrestin
recruited by S1P. Internalization experiments confirmed that cell surface
expression of the S1P1R but not the S1P3R was reduced following a pulse exposure
to FTY720-P, which is metabolically stable unlike S1P. CONCLUSIONS AND
IMPLICATIONS: FTY720-P and S1P activation of the S1P1R results in receptor
internalization as a consequence of an efficient recruitment of ?-arrestin. The
combination of slow off-rate, efficacious ?-arrestin recruitment and metabolic
stability all contribute to FTY720-P's ability to promote prolonged S1P1R
internalization and may be critical factors in its efficacy in the clinic.
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