Blockade of pancreatic polypeptide-sensitive neuropeptide Y (NPY) receptors by agonist peptides is prevented by modulators of sodium transport. Implications for receptor signaling and regulation

Ligand binding to rodent pancreatic polypeptide-responding neuropeptide Y ( NPY) receptors there termed PP/NPY receptors), or to cloned Y-4 or Y-5 rece ptors. is selectively inhibited by amiloride, peptide or alkylating modulat ors of sodium transport. The PP/NPY and Y-4 receptors are also selectively blocked by human or rat pancreatic polypeptide (PP) and the blocking peptid es are not dissociated by high concentrations of alkali chlorides (which re store most of the binding of subtype-selective agonists to Y, and YZ sites) . The PP/NPY receptors: could also be blocked by NPY and related full-lengt h peptides, including Y-1-selective agonists (IC50 300-300 pM). The cloned Y-4 receptors from three species are much less sensitive to NPY or PYY. The sensitivity of both the PP/NPY sites and the Y-4 sites to Y-2-selective pe ptides is quite low. The ligand attachment to PP/NPY sites is also very sen sitive to peptidic Y-1 antagonist ((Cys(31),NVal(34)NPY(27-36))(2), which h owever blocks these sites at much higher molarities. Blockade of PP/NPY and Y-4 sites by agonist peptides can be largely prevented by NS-substituted a miloride modulators of Na+ transport, and by RFamide NRNFLRF.NH2, but not b y Ca2+ channel blockers, or by inhibitors of K+ transport. Protection of bo th PP/NPY and Y, sites against blockade by human or rat pancreatic polypept ide is also afforded by short N-terminally truncated NPY-related peptides. The above results are consistent with a stringent and selective activity re gulation for rabbit PP/NPY receptor(s) that may serve to differentiate agon ists and constrain signaling, and could involve transporter-like interactan ts. (C) 2001 Elsevier Science Inc. All rights reserved.