THE CLONED GUINEA-PIG PANCREATIC-POLYPEPTIDE RECEPTOR Y4 RESEMBLES MORE THE HUMAN Y4 THAN DOES THE RAT Y4

Pancreatic polypeptide (PP) is involved in gastrointestinal functions and forms, together with neuropeptide Y (NPY) and peptide YY (PYY), th e PP-fold family of peptides. The PP-binding receptor subtype Y4 has s o far been cloned in human, rat, and mouse, and displays extensive spe cies differences regarding sequence, pharmacology, and distribution. T o explore this variability further, we have cloned the Y4 receptor in the guinea pig, which is evolutionarily equally distantly related to b oth humans and rodents. The guinea pig Y4 receptor is 84% identical to the human Y4 receptor, but only 74-75% identical to the rat and mouse receptors. The two latter are 75-76% identical to human Y4. The guine a pig Y4 receptor bound I-125-hPP with a dissociation constant (K-d) o f 29+/-3 pM. The pharmacological profile of guinea pig Y4 has the foll owing rank order of potencies: PP > NPY approximate to PYY approximate to LP-NPY approximate to LP-PYY > NPY2-36 approximate to [D-Trp(32)]N PY. Thus, the guinea pig receptor is more similar to the human Y4 than to the rat Y4 both in sequence and pharmacology. This agrees with the greater identity between guinea pig and human PP compared to rat PP. These comparisons suggest that the rodent PPs and Y4 receptors have an accelerated replacement rate. (C) 1998 Elsevier Science B.V. All righ ts reserved.