Differences in the Length of the Carboxyl Terminus Mediate Functional Properties of Neurokinin-1 Receptor

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Aug 21

PMID 18713853

Citations 55

Authors

Jian-Ping Lai

Saien Lai

Florin Tuluc

Morris F Tansky

Laurie E Kilpatrick

Susan E Leeman

Steven D Douglas

Affiliations

Soon will be listed here.

Abstract

The neurokinin-1 receptor (NK1R) has two naturally occurring forms that differ in the length of the carboxyl terminus: a full-length receptor consisting of 407 aa and a truncated receptor consisting of 311 aa. We examined whether there are differential signaling properties attributable to the carboxyl terminus of this receptor by using stably transfected human embryonic kidney (HEK293) cell lines that express either full-length or truncated NK1R. Substance P (SP) specifically triggered intracellular calcium increase in HEK293 cells expressing full-length NK1R but had no effect in the cells expressing the truncated NK1R. In addition, in cells expressing full-length NK1R, SP activated NF-kappaB and IL-8 mRNA expression, but in cells expressing the truncated NK1R, SP did not activate NF-kappaB, and it decreased IL-8 mRNA expression. In cells expressing full-length NK1R, SP stimulated phosphorylation of PKCdelta but inhibited phosphorylation of PKCdelta in cells expressing truncated NK1R. There are also differences in the timing of SP-induced ERK activation in cells expressing the two different forms of the receptor. Full-length NK1R activation of ERK was rapid (peak within 1-2 min), whereas truncated NK1R-mediated activation was slower (peak at 20-30 min). Thus, the carboxyl terminus of NK1R is the structural basis for differences in the functional properties of the full-length and truncated NK1R. These differences may provide important information toward the design of new NK1R receptor antagonists.

Citing Articles

Alternative Splicing at the Crossroad of Inflammatory Bowel Diseases and Colitis-Associated Colon Cancer.

Matos P, Jordan P Cancers (Basel). 2025; 17(2).

PMID: 39858001 PMC: 11764256. DOI: 10.3390/cancers17020219.

Cellular metabolism of substance P produces neurokinin-1 receptor peptide agonists with diminished cyclic AMP signaling.

Kriska T, Natarajan J, Herrnreiter A, Park S, Pfister S, Thomas M Am J Physiol Cell Physiol. 2024; 327(1):C151-C167.

PMID: 38798270 PMC: 11371325. DOI: 10.1152/ajpcell.00103.2024.

Electroacupuncture on Baihui (DU20) and Xuehai (SP10) acupoints alleviates psoriatic inflammation by regulating neurotransmitter substance P- Neurokinin-1 receptor signaling.

Qi C, Feng F, Guo J, Liu Y, Guo X, Meng Y J Tradit Complement Med. 2024; 14(1):91-100.

PMID: 38223807 PMC: 10785156. DOI: 10.1016/j.jtcme.2023.07.005.

The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant.

Covenas R, Rodriguez F, Robinson P, Munoz M Int J Mol Sci. 2023; 24(21).

PMID: 37958914 PMC: 10650658. DOI: 10.3390/ijms242115936.

The use of SP/Neurokinin-1 as a Therapeutic Target in Colon and Rectal Cancer.

Martin-Garcia D, Tellez T, Redondo M, Garcia-Aranda M Curr Med Chem. 2023; 31(39):6487-6509.

PMID: 37861026 DOI: 10.2174/0109298673261625230924114406.

References

Chang M, Leeman S . Isolation of a sialogogic peptide from bovine hypothalamic tissue and its characterization as substance P. J Biol Chem. 1970; 245(18):4784-90. View

Karagiannides I, Kokkotou E, Tansky M, Tchkonia T, Giorgadze N, OBrien M . Induction of colitis causes inflammatory responses in fat depots: evidence for substance P pathways in human mesenteric preadipocytes. Proc Natl Acad Sci U S A. 2006; 103(13):5207-12. PMC: 1458819. DOI: 10.1073/pnas.0600821103. View

Roush E, Kwatra M . Human substance P receptor expressed in Chinese hamster ovary cells directly activates G(alpha q/11), G(alpha s), G(alpha o). FEBS Lett. 1998; 428(3):291-4. DOI: 10.1016/s0014-5793(98)00553-5. View

Takeda Y, Chou K, Takeda J, Sachais B, Krause J . Molecular cloning, structural characterization and functional expression of the human substance P receptor. Biochem Biophys Res Commun. 1991; 179(3):1232-40. DOI: 10.1016/0006-291x(91)91704-g. View

Tansky M, Pothoulakis C, Leeman S . Functional consequences of alteration of N-linked glycosylation sites on the neurokinin 1 receptor. Proc Natl Acad Sci U S A. 2007; 104(25):10691-6. PMC: 1965574. DOI: 10.1073/pnas.0703394104. View

Baker S, Morris J, Gibbins I . Cloning of a C-terminally truncated NK-1 receptor from guinea-pig nervous system. Brain Res Mol Brain Res. 2003; 111(1-2):136-47. DOI: 10.1016/s0169-328x(03)00002-0. View

Chen F, Castranova V, Shi X, Demers L . New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem. 1999; 45(1):7-17. View

Derocq J, Segui M, Blazy C, Emonds-Alt X, Le Fur G, Brelire J . Effect of substance P on cytokine production by human astrocytic cells and blood mononuclear cells: characterization of novel tachykinin receptor antagonists. FEBS Lett. 1996; 399(3):321-5. DOI: 10.1016/s0014-5793(96)01346-4. View

Lai J, Douglas S, Wang Y, Ho W . Real-time reverse transcription-PCR quantitation of substance P receptor (NK-1R) mRNA. Clin Diagn Lab Immunol. 2005; 12(4):537-41. PMC: 1074379. DOI: 10.1128/CDLI.12.4.537-541.2005. View

10.

Holst B, Hastrup H, Raffetseder U, Martini L, Schwartz T . Two active molecular phenotypes of the tachykinin NK1 receptor revealed by G-protein fusions and mutagenesis. J Biol Chem. 2001; 276(23):19793-9. DOI: 10.1074/jbc.M100621200. View

11.

Hopkins B, Powell S, Danks P, Briggs I, Graham A . Isolation and characterisation of the human lung NK-1 receptor cDNA. Biochem Biophys Res Commun. 1991; 180(2):1110-7. DOI: 10.1016/s0006-291x(05)81181-7. View

12.

DeFea K, Vaughn Z, OBryan E, Nishijima D, Dery O, Bunnett N . The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta -arrestin-dependent scaffolding complex. Proc Natl Acad Sci U S A. 2000; 97(20):11086-91. PMC: 27152. DOI: 10.1073/pnas.190276697. View

13.

Gerard N, Garraway L, Eddy Jr R, Shows T, Iijima H, Paquet J . Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. Biochemistry. 1991; 30(44):10640-6. DOI: 10.1021/bi00108a006. View

14.

Yamaguchi K, Richardson M, Bigner D, Kwatra M . Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCdelta. Cancer Chemother Pharmacol. 2005; 56(6):585-93. DOI: 10.1007/s00280-005-1030-3. View

15.

Silver M, Nucci N, Root A, Reed K, Sower S . Cloning and characterization of a functional type II gonadotropin-releasing hormone receptor with a lengthy carboxy-terminal tail from an ancestral vertebrate, the sea lamprey. Endocrinology. 2005; 146(8):3351-61. DOI: 10.1210/en.2005-0305. View

16.

Chen F . Arresting NF-kappaB by beta-arrestin2. Cell Death Differ. 2004; 11(11):1155-6. DOI: 10.1038/sj.cdd.4401496. View

17.

Tran M, Lausch R, Oakes J . Substance P differentially stimulates IL-8 synthesis in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2000; 41(12):3871-7. View

18.

Palma C, Manzini S . Substance P induces secretion of immunomodulatory cytokines by human astrocytoma cells. J Neuroimmunol. 1998; 81(1-2):127-37. DOI: 10.1016/s0165-5728(97)00167-7. View

19.

Williams R, Zou X, Hoyle G . Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-kappaB via a G(q)-dependent pathway. Am J Physiol Lung Cell Mol Physiol. 2006; 292(2):L430-7. DOI: 10.1152/ajplung.00475.2005. View

20.

Lieb K, Fiebich B, Berger M, Bauer J, Schulze-Osthoff K . The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells. J Immunol. 1997; 159(10):4952-8. View