Increased plasma membrane expression of human follicle-stimulating hormone receptor by a small molecule thienopyr(im)idine

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:298

Article

Janovick, Jo Ann¹  Maya-Nunez, Guadalupe^1,2  Ulloa-Aguirre, Alfredo²  Huhtaniemi, Ilpo T.³  Dias, James A.⁴  Verbost, Pieter⁵  Conn, P. Michael^1,2,6,7 

[1] ONPRC, OHSU, Beaverton, OR 97006 USA

[2] Inst Mexicano Seguro Social, Hosp Ginecobstet Luis Castelazo Ayala, Res Unit Reprod Med, Mexico City, DF, Mexico

[3] Univ London Imperial Coll Sci Technol & Med, Dept Reprod Biol, London W12 NN, England

[4] New York State Dept Hlth, Wadsworth Ctr, David Axelrod Inst, Albany, NY 12208 USA

[5] Schering Plough Corp, Dept Pharmacol, NL-5340 BH Oss, Netherlands

[6] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR USA

[7] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR USA

关键词: FSH receptor;    Pharmacoperone;    Peptidomimetic;    Small molecule;    GPCR;    Receptor;    Therapeutics;   

DOI  :  10.1016/j.mce.2008.09.015

来源: Elsevier

【 摘 要 】

A thienopyr(im)idine (Org41841) activates the luteinizing hormone (LH) receptor but does not compete with the natural ligand binding site and does not show agonistic action on the follicle-stimulating hormone receptor (hFSHR) at sub-millimolar concentrations. When this drug is preincubated at sub-micromolar concentrations with host cells expressing the hFSHR, and then washed out, binding analysis and assessment of receptor-effector coupling show that it increases plasma membrane expression of the hFSHR. Real-time PCR shows that this effect did not result from increased hFSHR mRNA accumulation. It is possible that Org41841 behaves as a pharmacoperone, a drug which increases the percentage of newly synthesized receptor routing to the membrane. Like pharmacoperones for other receptors, this drug was able to rescue a particular mutant hFSHR (A(189)V) associated with misrouting and endoplasmic reticulum retention, although other mutants could not be rescued. This is potentially the first member of the pharmacoperone drug class which binds at a site that is distinctive from the ligand binding site. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

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