Identification, structure, and agonist design of an androgen membrane receptor

Yang Z; Ping YQ; Wang MW; Zhang C; Zhou SH; Xi YT; Zhu KK; Ding W; Zhang QY; Song ZC; Zhao RJ; He ZL; Wang MX; Qi L; Ullmann C; Ricken A; Schoneberg T; Gan ZJ; Yu X; Xiao P; Yi F; Liebscher I; Sun JP

doi:10.1530/ey.22.6.2

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 6.2 | DOI: 10.1530/ey.22.6.2

ESPEYB25 6. DSD and Gender Incongruence DSD Papers: Recent Information about Nuclear Receptor Genes Associated with Sexual Development (3 abstracts)

6.2. Identification, structure, and agonist design of an androgen membrane receptor

Yang Z , Ping YQ , Wang MW , Zhang C , Zhou SH , Xi YT , Zhu KK , Ding W , Zhang QY , Song ZC , Zhao RJ , He ZL , Wang MX , Qi L , Ullmann C , Ricken A , Schöneberg T , Gan ZJ , Yu X , Xiao P , Yi F , Liebscher I & Sun JP

Cell. 2025 Mar 20;188(6):1589-1604.e24. doi: 10.1016/j.cell.2025.01.006

Brief summary: This study identified GPR133, an adhesion type G protein coupled receptor, as a functional membrane receptor for the androgen 5α-dihydrotestosterone (5α-DHT). When activated by 5α-DHT in muscle cells, GPR133 increases intracellular cAMP levels, improving muscle strength. Cryo-electron microscopy elucidated the structural basis of steroid recognition by GPR133, revealing key motifs ("Φ(F/l)^2.64–F^3.40–W^6.53" and "F^7.42××N/D^7.46") within adhesion G protein-coupled receptors (GPCRs) that bind the hydrophobic steroid core and polar groups.

Further, the authors used computational screening to design AP503, a selective small-molecule agonist for GPR133. AP503 replicated the muscle-strengthening benefits of androgens without the typical side effects mediated by nuclear androgen receptors. This work positions GPR133 as a novel therapeutic target for enhancing skeletal muscle function.

Traditionally, the effects of androgens were thought to be mediated almost exclusively through nuclear androgen receptors (ARs). However, the rapid actions of 5α-DHT, unexplained by genomic mechanisms, suggest the existence of alternative signaling pathways. This work convincingly establishes GPR133 as a functional GPCR that mediates fast androgen responses and promotes muscle strength via PKA-dependent phosphorylation cascades.

The structural elucidation of GPR133 in complex with 5α-DHT in both high- and low-affinity binding states adds depth to our understanding of steroid-GPCR interactions. The physiological relevance of GPR133 in skeletal muscle function is well-demonstrated, with downstream signaling traced through MLCK2 and RYR1 activation, as well as the development of a synthetic agonist (AP503) that mimics androgen effects without activating AR.

AP503 represents a promising pharmacological tool that could bypass the side effects of traditional anabolic steroids. Its specificity for GPR133, sparing the AR, is particularly important for developing safer therapies targeting muscle weakness or sarcopenia. However, while the study identifies GPR133 as a key membrane receptor for 5α-DHT, the muscle-strengthening effect was not completely abolished in Gpr133 knockout mice. This strongly suggests the involvement of other yet unidentified, membrane receptors or compensatory pathways. A comprehensive mapping of potential additional GPCRs responsive to androgens is warranted. Furthermore, although AP503 showed efficacy in muscle strength enhancement in preclinical models, its safety, efficacy, and long-term impact in clinically relevant modelsremain unexplored, particularly aging or disease states like sarcopenia. Future studies are crucial for evaluating the translational potential of this compound. However, the findings lay an important foundation for the development of next-generation androgenic therapies with reduced adverse effects.