Desensitization of the Human Motilin Receptor by Motilides

Abstract

Tachyphylaxis may have contributed to the failure of the motilide

Characterization of Agonist-Induced Motilin Receptor Trafficking and Its Implications for Tachyphylaxis

“…This strategy did not seem to substantially alter MR sensitivity to ligand (Fig. 1C) or internalization after stimulation (Thielemans et al, 2005), similar to reports for other GPCRs (Kallal et al, 1998;Milligan, 1999;Kallal and Benovic, 2000). Its primary advantage is that it enables automated analysis of receptor endocytosis directly as opposed to indirect methods that follow GPCR trafficking via the redistribution of ␤-arrestin-GFP chimeras (Oakley et al, 2002).…”

“…at ASPET Journals on May 11, 2018 molpharm.aspetjournals.org strated that agonist potency alone is not the sole determinant for its ability to desensitize, internalize, and resensitize the motilin receptor (Thielemans et al, 2005). The results presented herein are consistent with these findings, demonstrating that ligand potency and tachyphylaxis properties are not necessarily linked; instead, we find a correlation between prolonged receptor internalization, delayed redistribution to the plasma membrane and tachyphylaxis.…”

“…The Cellomics Array Scan data analysis showed that dose-response saturation occurred at 80 nM motilin. The half-maximal effective motilin concentration (EC 50 ) for receptor internalization was 19 nM, which compares well with the Ca 2ϩ -signaling EC 50 of 9.2 nM reported for a similar MR-GFP chimera (Thielemans et al, 2005).…”

“…Such clinical evidence of functional motilin receptor desensitization has been reproduced in cell cultures using ABT-229 and other agonists (Li et al, 2004). More recently, by conducting a series of elegant structure-activity relationship experiments, Thielemans et al (2005) were able to identify a specific hydroxyl group within the ABT-229 molecule that seems to mediate the majority of its MR-desensitizing properties. Furthermore, the authors demon-…”

“…Patients treated with ABT-229 in clinical trials, however, experienced a decrease in response after repeated drug exposure (Talley et al, 2000;Netzer et al, 2002). It was proposed that motilin receptor desensitization, also termed tachyphylaxis, may have contributed to clinical failure (Tack and Peeters, 2001), and recent publications seem to support this hypothesis based on agonist-induced Ca 2ϩ measurements in cell culture experiments (Li et al, 2004;Thielemans et al, 2005).…”