Structure-Function Relationships in the Neuropeptide S Receptor

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 (Emax) 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. 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 (Emax) 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. Asthma is a multifactorial disease with both genetic and environmental components that is characterized by an exaggerated immune response induced upon exposure to antigens. The disease has become a major public health concern as its incidence has increased dramatically in recent years, particularly in developed countries (for a recent review, see Ref. 1Lilly C.M. J. Allergy Clin. Immunol. 2005; 115: S526-S531Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Studies in animal models have identified several genes and proteins that contribute to the asthmatic phenotype, although a complete understanding of the interplay between these factors, and their role in human disease, remains elusive (2Epstein M.M. Int. Arch. Allergy Immunol. 2004; 133: 84-100Crossref PubMed Scopus (120) Google Scholar). A number of genetic-linkage studies have recently been carried out to identify possible therapeutic targets for asthma that are relevant in man. One approach, involving whole genome scanning followed by refined genetic mapping, has led to the recent identification of four specific candidate genes (3Allen M. Heinzmann A. Noguchi E. Abecasis G. Broxholme J. Ponting C.P. Bhattacharyya S. Tinsley J. Zhang Y. Holt R. Jones E.Y. Lench N. Carey A. Jones H. Dickens N.J. Dimon C. Nicholls R. Baker C. Xue L. Townsend E. Kabesch M. Weiland S.K. Carr D. von Mutius E. Adcock I.M. Barnes P.J. Lathrop G.M. Edwards M. Moffatt M.F. Cookson W.O. Nat. 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Pulleyn L. Barnes P.J. Harper J.I. Abecasis G. Cardon L. White M. Burton J. Matthews L. Mott R. Ross M. Cox R. Moffatt M.F. Cookson W.O. Nat. Genet. 2003; 34: 181-186Crossref PubMed Scopus (277) Google Scholar). One of these, GPR154, encoding neuropeptide S receptor (NPSR) 4The abbreviations used are: NPSR, neuropeptide S receptor; CHO, Chinese hamster ovary; NMR, nuclear magnetic resonance; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect spectroscopy; NPS, neuropeptide S; TOCSY, total correlated spectroscopy; WT, wild type; HEK, human embryonic kidney; ELISA, enzyme-linked immunosorbent assay. 4The abbreviations used are: NPSR, neuropeptide S receptor; CHO, Chinese hamster ovary; NMR, nuclear magnetic resonance; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect spectroscopy; NPS, neuropeptide S; TOCSY, total correlated spectroscopy; WT, wild type; HEK, human embryonic kidney; ELISA, enzyme-linked immunosorbent assay. (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar, 7Xu Y.L. Reinscheid R.K. Huitron-Resendiz S. Clark S.D. Wang Z. Lin S.H. Brucher F.A. Zeng J. Ly N.K. Henriksen S.J. de Lecea L. Civelli O. Neuron. 2004; 43: 487-497Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar), also known as G protein receptor for asthma susceptibility (GPRA) (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar), GPR154 (8Gloriam D.E. Schioth H.B. Fredriksson R. Biochim. Biophys. Acta. 2005; 1722: 235-246Crossref PubMed Scopus (59) Google Scholar), and vasopressin receptor-related receptor 1 (VRR1) (9Gupte J. Cutler G. Chen J.L. Tian H. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 1508-1513Crossref PubMed Scopus (49) Google Scholar), has been confirmed as an asthma-linked gene in five distinct Caucasian populations (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar, 10Kormann M.S. Carr D. Klopp N. Illig T. Leupold W. Fritzsch C. Weiland S.K. von Mutius E. Kabesch M. Am. J. Respir. Crit. Care Med. 2005; 171: 1358-1362Crossref PubMed Scopus (109) Google Scholar, 11Melen E. Bruce S. Doekes G. Kabesch M. Laitinen T. Lauener R. Lindgren C.M. Riedler J. Scheynius A. Hage-Hamsten M. Kere J. Pershagen G. Wickman M. Nyberg F. Am. J. Respir. Crit. Care Med. 2005; 171: PubMed Scopus Google Scholar). The gene for NPSR at that in their (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar, J. Pulkkinen V. Rehn M. Pirskanen A. A. Laitinen A. Laitinen L.A. Kere J. Laitinen T. Am. J. Respir. 2005; PubMed Scopus Google and are to as and to and (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar), A number of single nucleotide polymorphisms in the NPSR are associated with and (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar, 10Kormann M.S. Carr D. Klopp N. Illig T. Leupold W. Fritzsch C. Weiland S.K. von Mutius E. Kabesch M. Am. J. Respir. Crit. Care Med. 2005; 171: 1358-1362Crossref PubMed Scopus (109) Google Scholar, 11Melen E. Bruce S. Doekes G. Kabesch M. Laitinen T. Lauener R. Lindgren C.M. Riedler J. Scheynius A. Hage-Hamsten M. Kere J. Pershagen G. Wickman M. Nyberg F. Am. J. Respir. Crit. Care Med. 2005; 171: PubMed Scopus Google Scholar). One of these single nucleotide polymorphisms is in the region of the gene and results in mutation of residue 107 to (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar). is known the and of NPSR. is a peptide known as neuropeptide S (NPS) of its expression in the and its putative role in Y.L. Reinscheid R.K. Huitron-Resendiz S. Clark S.D. Wang Z. Lin S.H. Brucher F.A. Zeng J. Ly N.K. Henriksen S.J. de Lecea L. Civelli O. Neuron. 2004; 43: 487-497Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar). of NPSR by NPS results in increased and leading to the that is to and proteins Y.L. Reinscheid R.K. Huitron-Resendiz S. Clark S.D. Wang Z. Lin S.H. Brucher F.A. Zeng J. Ly N.K. Henriksen S.J. de Lecea L. Civelli O. Neuron. 2004; 43: 487-497Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar, J. Cutler G. Chen J.L. Tian H. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 1508-1513Crossref PubMed Scopus (49) Google Scholar). the genetic that NPSR is involved in has been that expression of the the is increased in and of with (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar, J. Pulkkinen V. Rehn M. Pirskanen A. A. Laitinen A. Laitinen L.A. Kere J. Laitinen T. Am. J. Respir. 2005; PubMed Scopus Google Scholar). has also been shown that NPSR is in a of asthma (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar). that the of NPSR is in a of and in to the J. Pulkkinen V. Rehn M. Pirskanen A. A. Laitinen A. Laitinen L.A. Kere J. Laitinen T. Am. J. Respir. 2005; PubMed Scopus Google Scholar), although studies have shown that expression of the receptor is to the in particular the and the Y.L. Reinscheid R.K. Huitron-Resendiz S. Clark S.D. Wang Z. Lin S.H. Brucher F.A. Zeng J. Ly N.K. Henriksen S.J. de Lecea L. Civelli O. Neuron. 2004; 43: 487-497Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar, J. Cutler G. Chen J.L. Tian H. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 1508-1513Crossref PubMed Scopus (49) Google Scholar). with this of NPSR has been shown to be involved in Y.L. Reinscheid R.K. Huitron-Resendiz S. Clark S.D. Wang Z. Lin S.H. Brucher F.A. Zeng J. Ly N.K. Henriksen S.J. de Lecea L. Civelli O. Neuron. 2004; 43: 487-497Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar), and B. B. A. Biophys. 2005; PubMed Scopus Google in The structural of NPSR activation by NPS are for the part A recent the to the NH2-terminal of the peptide and that the N107I variant of NPSR is a mutant R.K. Y.L. N. Zeng J. S. R. Wang Z. Civelli O. J. 2005; PubMed Scopus Google Scholar). to relationships within the receptor and its as as to the molecular basis for the functional of the N107I identify the key residues in NPS involved in activation of NPSR as as that the N107I mutation both efficacy as as of the receptor to the of NPSR a by the and the a and a at the and a at the The the by in a first of the to the region of the NPSR by the as and a by and of the and in a of the and to the The and the by mutagenesis the the and the and of the NPSR by the and which a a peptide and a at the of the J. Full Text PDF PubMed Google Scholar). into the L.A. PubMed Scopus Google at the and their confirmed by the the of and through of Chinese hamster with the for the with to a and identified by single in a the to to and their in the in enzyme-linked immunosorbent as a with the at the by a as C.M. J. 2002; PubMed Scopus Google Scholar). The of confirmed to be by a as the and a as the the protein carried out as N. G.M. M. S. Y. R.W. Immunol. 2005; PubMed Scopus Google Scholar), with the the NPSR for and in and with of the and for at in the of the of in and to the and at and for a total of are as the between the maximal and the the of at which is are as S.D. of magnetic at a of a with a NPS at in in to at The in by an the with the of total correlated A. J. Scholar, L. J. Scopus Google and nuclear Overhauser effect J. P. J. Scopus Google K. of and Scholar). in the for J. Scholar). A. J. Scholar, R. T. J. with 1 in and in of with an R. T. J. for a of by a a to the by a and to by 1 to a of by of the the and with 1 in and in with The as a with a at to at a of for 5 with a of for and the peptide by The to by is the residue by number of peptide is in and is in into the which is upon the of PubMed Scopus Google Scholar, PubMed Scopus Google for of in for and with of the NPSR as with in and with of in 1 1 in and in the of NPS the of for at with and in the of for at by a and in for and for and with the NPSR as carried out as of in in for and with in for in the of and with in with the and an with and of the as the by at of and to with of NPSR has been that a single nucleotide polymorphism leading to mutation of residue to in NPSR is associated with an increased for asthma (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar). shown that this mutation causes an increase in the potency of NPS for NPSR R.K. Y.L. N. Zeng J. S. R. Wang Z. Civelli O. J. 2005; PubMed Scopus Google Scholar). To the we of the wild and N107I of both and in of shown in NPS with a potency its is also for and and confirmed in A of the in their potency for NPS, of the of residue 107 of NPS NPSR in at in populations of to receptor to receptor to receptor to receptor to receptor in a of the molecular basis for the functional between the and N107I we first to structure-function relationships in the receptor and its an approach, we the of the peptide by for the peptide with the of and K. of and Scholar). characterization by studies. shown in the region of the a of to to the of between and which be of the of the of these with in the region spanning these the and which are of a with of the peptide a the and the of a nascent helix residue to which may a upon receptor and Ref. M. J. PubMed Scopus Google Scholar). The putative of NPS such a helix is shown in of in the role of specific residues within NPS, we carried out mutagenesis of the peptide and the effect of these NPSR activation in the the assay. of for NPS and mutant are shown in A and a of the for is shown in and The results that residues in the NH2-terminal third of the peptide are necessary and sufficient for receptor activation. of the residues has limited effect the potency of the peptide, is to and the first NH2-terminal residues results in and are with both NPS and peptide that residues in this although for receptor of by of human NPS. in the as and the are shown in activation by NPS is the S.D. of of mutant are WT, activation by NPS is the S.D. of are WT, of for NPS mutant is the of at for peptide and to the shown in for which be to and of a maximal and are shown as an of of maximal for these mutant at a of of mutant NPS and in single of confirmed in of be to are shown as to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, to peptide the receptor variant, in a To the role of residues in the NH2-terminal of NPS, we residues 1 to with and the of the to shown in and of residues and with results in to complete of the peptide, as the with the with the NPS these results that the first in particular residues Phe-2, Arg-3, Asn-4, and Val-6, are necessary for receptor residue is and the of the between NPSR and in identified of NPS that are for NPSR we to the possible role of residue the and activation. that we see an of the mutant activation this residue is involved in receptor activation the NH2-terminal and the N107I variant of shown in 5 shown in the of activation with the NH2-terminal is with the N107I variant with its Whereas and have for that are and NPS, these are to the peptide a increase in for peptide the although of residues with results in to complete both receptor their in receptor the mutation is to with these results suggest that a key role in receptor activation and that its interaction with of NPS a regulatory role in in of the N107I in a the results suggest that the N107I mutation the of NPSR, to have effects by receptor at the the of NPSR for such we to the receptor with a the NH2-terminal of the to the expression of NPSR in which functional in shown and see Ref. R.K. Y.L. N. Zeng J. S. R. Wang Z. Civelli O. J. 2005; PubMed Scopus Google Scholar), we a number of for these studies. with we identified as the to expression of NPSR. with show a increase in in the of NPS with To the effect of the N107I mutation we first confirmed the of this variant in both the and in this and in to the in between the and N107I a increase in maximal activation (Emax) is also for the mutant with the the in in the and for and of NPS for the receptor with has been R.K. Y.L. N. Zeng J. S. R. Wang Z. Civelli O. J. 2005; PubMed Scopus Google Scholar). the we a in maximal between the suggesting that the N107I mutation expression of the of and N107I of NPSR and the of expression of the NPSR this expression and of the of shown in of with variant of a of N107I receptor at the of total receptor expression confirmed this by and total NPSR expression by and Our results are with a of in receptor for the N107I receptor with the To receptor receptor D. Sci. Full Text PDF PubMed Scopus Google in we with of to receptor and the of this the potency of NPS and its maximal efficacy (Emax) NPSR in the assay. To that receptor expression in this total number of we the total of for by with shown in with of to causes a increase in of receptor expression and NPS are shown in with of with to a total as is the S.D. of A is and in of to the shown in The structure-function relationships within NPSR and its and a molecular basis for the functional between the receptor and the asthma-linked mutant The of this variant of NPSR is associated with an increase in both the efficacy of its NPS with a in and in its expression to an increase in with the that the N107I mutation is associated with an increase in asthma susceptibility (4Laitinen T. Polvi A. Rydman P. Vendelin J. Pulkkinen V. Salmikangas P. Makela S. Rehn M. Pirskanen A. Rautanen A. Zucchelli M. Gullsten H. Leino M. Alenius H. Petays T. Haahtela T. Laitinen A. Laprise C. Hudson T.J. Laitinen L.A. Kere J. Science. 2004; 304: 300-304Crossref PubMed Scopus (379) Google Scholar, 10Kormann M.S. Carr D. Klopp N. Illig T. Leupold W. Fritzsch C. Weiland S.K. von Mutius E. Kabesch M. Am. J. Respir. Crit. Care Med. 2005; 171: 1358-1362Crossref PubMed Scopus (109) Google Scholar, 11Melen E. Bruce S. Doekes G. Kabesch M. Laitinen T. Lauener R. Lindgren C.M. Riedler J. Scheynius A. Hage-Hamsten M. Kere J. Pershagen G. Wickman M. Nyberg F. Am. J. Respir. Crit. Care Med. 2005; 171: PubMed Scopus Google Scholar), suggest that NPSR may be a therapeutic for the of this A first of this to structure-function relationships within NPSR and its structural characterization of the NPS peptide by and identified a putative nascent helix between residues and The for this region of NPS shown in is the that nascent are to into in such as in the of receptor M. J. PubMed Scopus Google Scholar). its this region of to have a role in receptor is for receptor activation a peptide in which of the region of NPS is is with the peptide the and and 5 and that the residues necessary and sufficient for receptor activation are in the NH2-terminal third of the with the mutagenesis studies and 5 and these results identify residues Phe-2, Arg-3, Asn-4, and as for receptor and to limited the between residues 5 and of NPS is necessary for receptor to have a in the of a peptide, residues in this region a in receptor and to and in and 5 and suggesting that this has an is particularly to this peptide is particularly the peptide peptide and and peptide is in the receptor and these effects are in the of the with the N107I variant of 5 and results are with an between residue 107 of NPSR and residue of NPS that receptor activation in in of the residues of NPS at the of with by of the region One possible structural for the in activation of the NPSR by peptide is that is between the residues in the variant of NPSR, which is to the The N107I variant, the be to with to the of with a of the interaction in the of the of an residue in the mutant first by Reinscheid and R.K. Y.L. N. Zeng J. S. R. Wang Z. Civelli O. J. 2005; PubMed Scopus Google and confirmed mutation of residue of NPSR to leads to an increase in the potency of NPS for the The of a expression has to that in to this increase in the maximal efficacy (Emax) of NPS is also increased the N107I variant with the also show that this increase in is to a of receptor of the mutant with the as by and the expression of is that of receptor expression by with of NPSR leads to in the the in with the N107I variant is to expression of NPSR, to in the potency of NPS its receptor, the expression of NPSR as the increase in potency is associated with a in the of NPS for NPSR see also Ref. R.K. Y.L. N. Zeng J. S. R. Wang Z. Civelli O. J. 2005; PubMed Scopus Google Scholar), to be to a in the efficacy of NPS, which is its to the receptor is is to that this is to the interaction between residue 107 of the receptor and the regulatory region of NPS, in particular residue as we have identified key residues in the NPSR receptor and NPS involved in receptor activation. results a for structural and functional studies this receptor and the molecular basis for the increased asthma susceptibility associated with the N107I variant of NPSR.

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