Pharmacological Characterization of Human and Murine Neuropeptide S Receptor Variants

• Published in: The Journal of pharmacology and experimental therapeutics 2005-12, Vol.315 (3), p.1338-1345
• Main Authors: Reinscheid, Rainer K, Xu, Yan-Ling, Okamura, Naoe, Zeng, Joanne, Chung, Shinjae, Pai, Rama, Wang, Zhiwei, Civelli, Olivier
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Asparagine - chemistry; Caco-2 Cells; Calcium - metabolism; Cell Division - drug effects; Cell Line; Cyclic AMP - analysis; Cyclic AMP - biosynthesis; Dose-Response Relationship, Drug; Exons; Genes, Reporter; Genetic Variation; HT29 Cells; Humans; Isoleucine - chemistry; Luciferases - metabolism; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neuropeptides - pharmacology; Phosphorylation - drug effects; Polymorphism, Genetic; Protein Isoforms - agonists; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Radioligand Assay; Receptors, Neuropeptide - agonists; Receptors, Neuropeptide - chemistry; Receptors, Neuropeptide - genetics; Receptors, Neuropeptide - metabolism; Structure-Activity Relationship
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.093427

We have recently shown that Neuropeptide S (NPS) can promote arousal and induce anxiolytic-like effects after central administration in rodents. Another study reported a number of natural polymorphisms in the human NPS receptor gene. Some of these polymorphisms were associated with increased risk of asthma and possibly other forms of atopic diseases, but the physiological consequences of the mutations remain unclear. One of the polymorphisms produces an Asn-Ile exchange in the first extracellular loop of the receptor protein, and a C-terminal splice variant of the NPS receptor was found overexpressed in human asthmatic airway tissue. We sought to study the pharmacology of the human receptor variants in comparison with the murine receptor protein. Here, we report that the N107I polymorphism in the human NPS receptor results in a gain-of-function characterized by an increase in agonist potency without changing binding affinity in NPSR Ile 107 . In contrast, the C-terminal splice variant of the human NPS receptor shows a pharmacological profile similar to NPSR Asn 107 . The mouse NPS receptor, which also carries an Ile residue at position 107, displays an intermediate pharmacological profile. Structure-activity relationship studies show that the amino terminus of NPS is critical for receptor activation. The altered pharmacology of the Ile 107 isoform of the human NPS receptor implies a mechanism of enhanced NPS signaling that might have physiological significance for brain function as well as peripheral tissues that express NPS receptors.