A strong candidate for I1R, known as imidazoline receptor antisera-selected protein (IRAS), has been cloned from human hippocampus [14] . hIRAS is a larger protein of 1504 amino acids consisting of an NH 2 -terminal phox (PX) domain, 5 putative leucine-rich repeats, a predicted coiledcoil domain, and a long COOH-terminal region. Several evidence supported the identity of native I1R and IRAS protein in tissue distributions, ligand binding properties, some cellular functions and downstream signal pathways [14] [15] [16] [17] [18] . The murine form of IRAS, Nischarin, truncated at the N-terminal 244 amino acids including the PX domain compared with the hIRAS, was a soluble cytosolic protein involved in cytoskeletal organization [19] . It has been shown that decreasing the expression of rat IRAS or Nischarin in PC12 rat pheochromocytoma cells could attenuate the activation of extracellular signal-regulated kinase (ERK) or reduce the radioligand binding to I1R, which further supported that hIRAS or Nischarin might serve as I1R itself, or at least a functional subunit of I1R [20] . Recently, Molderings et al. have reported that the "I1-imidazoline receptors" mediating effects of clonidine and moxonidine in PC12 and the transfected HEK293 cells belonged to the S1P-receptor family, in particular, representing a mixture of sphingosine-1-phosphate (S1P)1-and S1P3-receptors and/or heterodimers of both. It was then proposed that an increased expression of IRAS or Nischarin may improve the receptor-trafficking from cytosolic S1P-receptors to the cell membrane and thereby increase the number of binding sites in the plasma membrane for radioligand binding [21] . In our previous study, we also reported that IRAS mediated agmatine-induced inhibition of opioid dependence in morphine-dependent cells [22] . Despite intensive efforts, the molecular base of the I1R had not yet been elucidated.