Imperial College London
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ProfessorAylinHanyaloglu

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Professor in Molecular Medicine
 
 
 
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Contact

 

+44 (0)20 7594 2128a.hanyaloglu Website

 
 
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Assistant

 

Miss Kiran Dosanjh +44 (0)20 7594 2176

 
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Location

 

2009Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Sposini:2020:10.3389/fphar.2020.593492,
author = {Sposini, S and De, Pascali F and Richardson, R and Sayers, S and Perrais, D and Yu, H and Palmer, S and Nataraja, S and Reiter, E and Hanyaloglu, A},
doi = {10.3389/fphar.2020.593492},
journal = {Frontiers in Pharmacology},
title = {Pharmacological programming of endosomal signaling activated by small molecule ligands of the follicle stimulating hormone receptor},
url = {http://dx.doi.org/10.3389/fphar.2020.593492},
volume = {11},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Follicle-stimulating hormone receptor (FSHR) is a G protein-coupled receptor (GPCR) with pivotal roles in reproduction. One key mechanism dictating the signal activity of GPCRs is membrane trafficking. After binding its hormone FSH, FSHR undergoes internalization to very early endosomes (VEEs) for its acute signaling and sorting to a rapid recycling pathway. The VEE is a heterogeneous compartment containing the Adaptor Protein Phosphotyrosine Interacting with Pleckstrin homology Domain and Leucine Zipper 1 (APPL1) with distinct functions in regulating endosomal Gαs/cAMP signaling and rapid recycling. Low molecular weight (LMW) allosteric FSHR ligands were developed for use in assisted reproductive technology yet could also provide novel pharmacological tools to study FSHR. Given the critical nature of receptor internalization and endosomal signaling for FSHR activity, we assessed whether these compounds exhibit differential abilities to alter receptor endosomal trafficking and signaling within the VEE. Two chemically distinct LMW agonists (benzamide, termed B3 and thiazolidinone, termed T1) were employed. T1 was able to induce a greater level of cAMP than FSH and B3. As cAMP signaling drives gonadotrophin hormone receptor recycling, rapid exocytic events were evaluated at single event resolution. Strikingly, T1 was able to induce a 3-fold increase in recycling events compared to FSH and two-fold more compared to B3. As T1-induced internalization was only marginally greater, the dramatic increase in recycling and cAMP signaling may be due to additional mechanisms. All compounds exhibited a similar requirement for receptor internalization to increase cAMP and proportion of FSHR endosomes with active Gαs, suggesting regulation of cAMP signaling induced by T1 may be altered. APPL1 plays a central role for GPCRs targeted to the VEE, and indeed, loss of APPL1 inhibited FSH-induced recycling and increased endosomal cAMP signaling. While T1-induced FSHR recyclin
AU  - Sposini,S
AU  - De,Pascali F
AU  - Richardson,R
AU  - Sayers,S
AU  - Perrais,D
AU  - Yu,H
AU  - Palmer,S
AU  - Nataraja,S
AU  - Reiter,E
AU  - Hanyaloglu,A
DO  - 10.3389/fphar.2020.593492
PY  - 2020///
SN  - 1663-9812
TI  - Pharmacological programming of endosomal signaling activated by small molecule ligands of the follicle stimulating hormone receptor
T2  - Frontiers in Pharmacology
UR  - http://dx.doi.org/10.3389/fphar.2020.593492
UR  - http://hdl.handle.net/10044/1/84874
VL  - 11
ER  -
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