Interaction of NPY compounds with the rat glucocorticoid-induced receptor (GIR) reveals similarity to the NPY-Y2 receptor

The rat glucocorticoid-induced receptor (rGIR) is an orphan G protein-coupled receptor awaiting pharmacological characterization. Among known receptors, rGIR exhibits highest sequence similarity to the neuropeptide Y (NPY)-Y-2 receptor (38-40%). The pharmacological profile of rGIR was investigated using I-125-PYY3-36, a Y-2-preferring radioligand and several NPY analogs. rGIR displayed a similar displacement profile as reported for the Y-2 receptor, in that the Y-2-selective C terminus fragments of NPY and PYY (NPY3-36, and PYY3-36) showed high affinity binding and activation of rGIR (low nanomolar range). The rank order potency for displacement was NPY3-36 > PYY3-36=NPY > NPY13-36 > Ac, Leu NPY24-36 >[D-Trp(32)]-NPY > Leu(31), Pro(34)-NPY=hPP. NPY and Y-2-selective agonists NPY3-36 and PYY3-36 led to significant activation of S-35-GTP gamma S binding to rGIR transfected cells. BIIE0246, a specific Y-2 antagonist, displaced I-125-PYY3-36 binding to rGIR with high affinity (95 nM). Activation of S-35-GTP gamma S binding by Y-2-selective agonist in rGIR transfected cells was also completely abolished by BIIE0246. Our data report, for the first time, an interaction of NPY ligands with rGIR expressed in vitro, and indicate similarities between GIR and the NPY-Y-2 receptor. (c) 2007 Elsevier Inc. All rights reserved.