HE6 (GPR64) is a highly conserved, tissue-specific heptahelical receptor of the human epididymis. The seven transmembrane (TM7) domains are a hallmark of G-protein-coupled receptors (GPCRs) which have a proven history of being excellent therapeutic targets. Of all currently marketed drugs, >30% are modulators of specific heptahelical receptors, emphasizing the potential of HE6 as a target for pharmaceutical intervention. Targeted mutation of the mouse HE6 counterpart resulted in male infertility, further emphasizing its role as a candidate target for male contraception. However, the precise function of HE6, together with its potential ligand(s), and signal transduction pathways have remained largely unknown. On the basis of shared sequence motifs within the TM7 region, HE6 has been grouped into the B class of GPCRs. Within this class, HE6 belongs to the 'large N-termini' family-B seven-transmembrane (LNB-TM7) receptors, also termed the adhesion-GPCRs. Members of this subgroup are 'orphan' receptors, and they all seem to be cleaved within a conserved GPCR proteolytic site (GPS) domain. The biological significance of the two-subunit architecture is still unknown. Clues to the function of HE6 within the epithelium of male excurrent ducts may come from its co-localisation with the apical actin cytoskeleton and from the down-regulation in "knockout" male mice of various proteins specific to the initial segment.
