HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 34, 24704-24712, August 25, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/34/24704    most recent M603691200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bernier, V. Articles by Therien, A. G. Search for Related Content PubMed PubMed Citation Articles by Bernier, V. Articles by Therien, A. G. Social Bookmarking                      What's this?

Structure-Function Relationships in the Neuropeptide S Receptor

MOLECULAR CONSEQUENCES OF THE ASTHMA-ASSOCIATED MUTATION N107I^*

Virginie Bernier^||12, Rino Stocco¹, Michael J. Bogusky, Joseph G. Joyce^¶, Christine Parachoniak, Karl Grenier, Michael Arget, Marie-Claude Mathieu, Gary P. O'Neill, Deborah Slipetz^||, Michael A. Crackower, Christopher M. Tan^||, and Alex G. Therien³

From the Departments of Biochemistry and Molecular Biology and ^||Pharmacology, Merck Frosst Center for Therapeutic Research, Kirkland, Quebec H9H 3L1, Canada and the Departments of Medicinal Chemistry and ^¶Vaccine and Biologics Research, Merck & Co., West Point, Pennsylvania 19486

Neuropeptide S (NPS) and its receptor (NPSR) are thought to have a role in asthma pathogenesis; a number of single nucleotide polymorphisms within NPSR have been shown to be associated with an increased prevalance of asthma. One such single nucleotide polymorphism leads to the missense mutation N107I, which results in an increase in the potency of NPS for NPSR. To gain insight into structure-function relationships within NPS and NPSR, we first carried out a limited structural characterization of NPS and subjected the peptide to extensive mutagenesis studies. Our results show that the NH₂-terminal third of NPS, in particular residues Phe-2, Arg-3, Asn-4, and Val-6, are necessary and sufficient for activation of NPSR. Furthermore, part of a nascent helix within the peptide, spanning residues 5 through 13, acts as a regulatory region that inhibits receptor activation. Notably, this inhibition is absent in the asthma-linked N107I variant of NPSR, suggesting that residue 107 interacts with the aforementioned regulatory region of NPS. Whereas this interaction may be at the root of the increase in potency associated with the N107I variant, we show here that the mutation also causes an increase in cell-surface expression of the mutant receptor, leading to a concomitant increase in the maximal efficacy (E_max) of NPS. Our results identify the key residues of NPS involved in NPSR activation and suggest a molecular basis for the functional effects of the N107I mutation and for its putative pathophysiological link with asthma.

Received for publication, April 17, 2006 , and in revised form, June 20, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Recipient of an Industrial Research Fellowship from the National Sciences and Engineering Research Council.

³ To whom correspondence should be addressed: 16711 Trans Canada Hwy., Kirkland, Quebec H9H 3L1, Canada. Tel.: 514-428-3937; Fax: 514-428-8615; E-mail: alex_therien{at}merck.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				V. Camarda, A. Rizzi, C. Ruzza, S. Zucchini, G. Marzola, E. Marzola, R. Guerrini, S. Salvadori, R. K. Reinscheid, D. Regoli, et al. In Vitro and in Vivo Pharmacological Characterization of the Neuropeptide S Receptor Antagonist [D-Cys(tBu)5]Neuropeptide S J. Pharmacol. Exp. Ther., February 1, 2009; 328(2): 549 - 555. [Abstract] [Full Text] [PDF]

				J. Vendelin, S. Bruce, P. Holopainen, V. Pulkkinen, P. Rytila, A. Pirskanen, M. Rehn, T. Laitinen, L. A. Laitinen, T. Haahtela, et al. Downstream target genes of the neuropeptide S-NPSR1 pathway Hum. Mol. Genet., October 1, 2006; 15(19): 2923 - 2935. [Abstract] [Full Text] [PDF]