Full-length and truncated neurokinin-1 receptor expression and function during monocyte/macrophage differentiation

Lai, Jianping; Ho, Wen‐Zhe; Kilpatrick, Laurie E.; Wang, X.; Tuluc, Florin; Korchak, Helen M.; Douglas, Steven D.

doi:10.1073/pnas.0602563103

Cited by 85 publications

(106 citation statements)

References 60 publications

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“…Truncated NK1R may also interact with other GPCR in other cell functions. We have demonstrated, for example, that SP activation of the natural endogenous truncated NK1R primes CCL5-mediated calcium increases in undifferentiated THP-1 cells that express only the truncated NK1R (29), indicating an independent downstream signaling pathway for truncated NK1R. Activation of the truncated NK1R may also transduce its signals through G proteinindependent mechanisms as demonstrated by Ahn et al (26) in cells that express angiotensin II type 1A receptor.…”

Section: Discussionsupporting

confidence: 55%

“…Truncated forms of receptors also possess downstream pathways of signal transduction that may or may not be involved in full-length receptor signal transduction (34). In undifferentiated THP-1 cells that express only the truncated NK1R, SP does not trigger calcium increases in these cells but primes CCL5-mediated calcium increases, indicating that the truncated NK1R has the capacity to interact with other GPCR and has its own unique downstream signal pathway(s) (29).…”

Section: Discussionmentioning

confidence: 99%

“…Intracellular calcium measurements were performed in fura-2-loaded cells by using Tsien's ratiometric method (36) as described in ref. 29. Peak intracellular calcium increases were determined and used to construct concentration-response curves.…”

Section: Methodsmentioning

confidence: 99%

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Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor

Lai

Tuluc

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The neurokinin-1 receptor (NK1R) has two naturally occurring forms that differ in the length of the carboxyl terminus: a fulllength 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-B and IL-8 mRNA expression, but in cells expressing the truncated NK1R, SP did not activate NF-B, and it decreased IL-8 mRNA expression. In cells expressing full-length NK1R, SP stimulated phosphorylation of PKC␦ but inhibited phosphorylation of PKC␦ in cells expressing truncated NK1R. There are also differences in the timing of SPinduced 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.G protein-coupled receptor ͉ cell signaling ͉ Substance P ͉ truncated neurokinin-1 ͉ calcium mobilization

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor

Lai

Tuluc

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…These isoforms have distinct signalling properties, with only the wild-type receptor being able to increase intracellular Ca 2+ concentration and activate the transcription factor NFκB, leading to increased expression of F o r R e v i e w O n l y mRNA for interleukin-8 [59]. In addition, compared to the wild-type receptor, the truncated NK 1 receptor variant may have an increased ability to interact with different G proteins, other GPCRs, or G protein-independent signalling pathways [59,63]. This could be of considerable importance in cells and tissues that have distinct expressions of the NK 1 receptor isoforms.…”

Section: Alternative Splicing Of Gpcr In Other Pathophysiological Conmentioning

confidence: 99%

“…[59][60][61][62][63][64] Neurokinin receptor 2 Exon exclusion Impaired ligand binding and signalling [65,66] Neuropeptide S receptor (GPRA) Alternative C-terminal exons, trancation Intracellular localization of truncated isoform [67] Opioid receptors Several Various Reviewed in [68] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Overview of GPCRs encoded by more than one exon. In the "pre-human genome era" it was assumed that more than 90% of human GPCRs were intronless [15].…”

Section: Closing Remarksmentioning

confidence: 99%

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

Markovic

Challiss

2009

Cell. Mol. Life Sci.

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Abstract. The G protein-coupled receptors (GPCRs) are a superfamily of transmembrane receptors that have a broad distribution and can collectively recognize a diverse array of ligands. Activation or inhibition of GPCR signalling can affect many (patho)physiological processes and consequently they are a major target for existing and emerging drug therapies.A common observation has been that the pharmacological, signalling and regulatory properties of GPCRs can vary in a cell-and tissue-specific manner. Such "phenotypic" diversity might be attributable to post-translational modifications and/or association of GPCRs with accessory proteins, however, post-transcriptional mechanisms are also likely to contribute. Although, approximately 50% of GPCR genes are intronless, those that possess introns can undergo alternative splicing, generating GPCR subtype isoforms that may differ in their pharmacological, signalling and regulatory properties. In this Review we shall highlight recent research into GPCR splice-variation, and discuss the potential consequences this might have for GPCR function in health and disease.

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Illuminating the structural basis of human neurokinin 1 receptor (NK1R) antagonism through classical all‐atoms molecular dynamics simulations

Mishra,

Rout,

Singh

et al. 2023

J of Cellular Biochemistry

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Advances in structural biology have bestowed insights into the pleiotropic effects of neurokinin 1 receptors (NK1R) in diverse patho‐physiological processes, thereby highlighting the potential therapeutic value of antagonists directed against NK1R. Herein, we investigate the mode of antagonist recognition to discern the obscure atomic facets germane for the function and molecular determinants of NK1R. To commence discernment of potent antagonists and the conformational changes in NK1R, induced upon antagonist binding, state‐of‐the‐art classical all‐atoms molecular dynamics (MD) simulations in lipid mimetic bilayers have been utilized. MD simulations of structural ensembles reveals the involvement of TM5 and TM6 in tight anchoring of antagonists through a network of interhelical hydrogen‐bonds, while, the extracellular loop 2 (ECL2) governs the overall size and nature of the pocket, thereby modulating NK1R. Consistent comparison between experiments and MD simulation results discerns the predominant role of TM3, TM4, and TM6 in lipid‐NK1R interaction. Correlation between hydrophobic index and helicity of TM domains elucidates their importance in maintaining the structural stability in addition to regulating NK1R antagonism. Taken together, we anticipate that our computational study marks a comprehensive structural basis of NK1R antagonism in lipid bilayers, which may facilitate designing of new therapeutics against associated diseases targeting human neurokinin receptors.

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Full-length and truncated neurokinin-1 receptor expression and function during monocyte/macrophage differentiation

Cited by 85 publications

References 60 publications

Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor

Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

Illuminating the structural basis of human neurokinin 1 receptor (NK1R) antagonism through classical all‐atoms molecular dynamics simulations

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