Membrane Androgen Receptors Unrelated to Nuclear Steroid Receptors

Rapid (nongenomic) membrane-initiated androgen actions have been described in nuclear androgen receptor-null cells. Four distinct proteins have been proposed as membrane androgen receptors (mARs) or sensors. Transient receptor potential melastatin 8 (TRPM8) is a calcium channel that acts as a pain receptor and mediates androgen- and menthol-induced increases in calcium levels and survival of prostate cancer cells. Testosterone (T) directly interacts with TRPM8, but extensive androgen receptor binding studies to confirm its role as an mAR are lacking. Oxoeicosanoid receptor 1 (OXER1) is highly expressed in prostate cancer tissues, and its major ligand, 5-oxoeicosatretraenoic acid (5-oxo-ETE), is a potent inducer of prostate cancer cell proliferation and survival. T competes for 5-oxo-ETE binding to OXER1 and antagonizes 5-oxo-ETE-mediated inhibition of cAMP production. However, OXER1 does not meet a traditional criterion for its designation as an mAR because T treatment alone does not alter cAMP signaling. GPRC6A is a class C G protein-coupled receptor activated by l-α-amino acids and is modulated by calcium. Although there has been controversy over the proposed role of T as a GPRC6A ligand, androgen induction of GPRC6A signaling has recently been confirmed by several researchers. ZIP9 belongs to the zinc transporter ZIP (SLC39A) family and displays specific T binding characteristic of an mAR. ZIP9 mediates androgen-dependent intracellular signaling and apoptosis of breast and prostate cancer cells through activation of G proteins. Androgen-signaling functions of ZIP9 have been confirmed in other cells, but the overall importance of ZIP9 in androgen physiology remains unclear. Here, the current status of these four proteins as mARs or sensors is critically reviewed.