Received for publication July 29, 2005.
Revised September 1, 2005.
Accepted for publication September 2, 2005.

Pharmacological Characterization of Human and Murine Neuropeptide S Receptor Variants

Abstract

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 second extracellular loop of the receptor protein and a C-terminal splice variant of the NPS receptor was found over-expressed 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 Asn¹⁰⁷Ile 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 Ile¹⁰⁷. In contrast, the C-terminal splice variant of the human NPS receptor shows a pharmacological profile similar to NPSR Asn¹⁰⁷. 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 Ile¹⁰⁷ 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.

Key words: asthma, gain-of-function, orphan receptor, polymorphism, second messenger, structure-activity

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