Membrane-associated androgen receptor (mAR) (mAR)

The membrane-associated androgen receptor (mAR) is a functional class of cell-surface receptors that mediate rapid, non-genomic signaling in response to androgens such as testosterone and dihydrotestosterone (DHT). Unlike the classical nuclear androgen receptor (AR), which primarily functions as a ligand-activated transcription factor, mARs are localized to the plasma membrane—often within lipid rafts—and trigger immediate intracellular signaling cascades upon ligand binding [1, 3, 15]. Several distinct proteins have been identified as mARs, including the zinc transporter ZIP9 (SLC39A9), the G protein-coupled receptor GPRC6A, the oxoeicosanoid receptor 1 (OXER1), and the ion channel TRPM8, as well as specific splice variants of the classical AR like AR8 and AR45 [2, 6, 10]. These receptors play critical roles in various physiological and pathological processes, including the regulation of zinc and calcium levels, cell migration, and apoptosis [1, 15]. In the context of disease, mARs are significantly involved in the progression of hormone-dependent cancers, particularly prostate and breast cancer [4, 11]. They are often expressed or even upregulated in castration-resistant prostate cancer (CRPC), where they can sustain tumor growth and survival even when androgen levels are low or when the classical AR is inhibited [10, 12]. Because many mARs do not respond to conventional antiandrogens like bicalutamide or enzalutamide, they represent a novel frontier for therapeutic intervention [4, 12]. Current research focuses on developing specific inhibitors or utilizing mAR-mediated pathways to induce apoptosis in cancer cells, while also considering the potential safety concerns related to systemic zinc homeostasis and metabolic regulation [8, 15].

Other names

Membrane androgen receptormARZIP9SLC39A9GPRC6AOXER1AR8AR45Membrane-initiated androgen receptor

Non-genomic signaling through activation of intracellular kinase cascades (MAPK/ERK, PI3K/Akt), modulation of ion flux (calcium, zinc), and interaction with G proteins.