Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The G protein-coupled receptor (GPCR) for thrombin, protease-activated receptor-1 (PAR1), is activated when thrombin cleaves its amino-terminal exodomain. The irreversibility of this proteolytic mechanism raises the question of how desensitization and resensitization are accomplished for thrombin signaling. PAR1 is phosphorylated, uncoupled from signaling, and internalized after activation like classic GPCRs. However, unlike classic GPCRs, which internalize and recycle, activated PAR1 is sorted to lysosomes. To identify the signals that specify the distinct sorting of PAR1, we constructed chimeras between PAR1 and the substance P receptor. Wild-type substance P receptor internalized and recycled after activation; PAR1 bearing the cytoplasmic tail of the substance P receptor (P/S) behaved similarly. By contrast, wild-type PAR1 and a substance P receptor bearing the cytoplasmic tail of PAR1 (S/P) sorted to lysosomes after activation. Consistent with these observations, PAR1 and the S/P chimera were effectively down-regulated by their respective agonists as assessed by both receptor protein levels and signaling. Substance P receptor and the P/S chimera showed little down-regulation. These data suggest that the cytoplasmic tails of PAR1 and substance P receptor specify their distinct intracellular sorting patterns after activation and internalization. Moreover, by altering the trafficking fates of PAR1 and substance P receptor, one can dictate the efficiency with which a cell maintains responsiveness to PAR1 or substance P receptor agonists over time.
 ...
PMID:The cytoplasmic tails of protease-activated receptor-1 and substance P receptor specify sorting to lysosomes versus recycling. 989 Sep 84

The substance P receptor (SPR) is a G protein-coupled receptor (GPCR) that plays a key role in pain regulation. The SPR desensitizes in the continued presence of agonist, presumably via mechanisms that implicate G protein-coupled receptor kinases (GRKs) and beta-arrestins. The temporal relationship of these proposed biochemical events has never been established for any GPCR other than rhodopsin beyond the resolution provided by biochemical assays. We investigate the real-time activation and desensitization of the human SPR in live HEK293 cells using green fluorescent protein conjugates of protein kinase C, GRK2, and beta-arrestin 2. The translocation of protein kinase C betaII-green fluorescent protein to and from the plasma membrane in response to substance P indicates that the human SPR becomes activated within seconds of agonist exposure, and the response desensitizes within 30 s. This desensitization process coincides with a redistribution of GRK2 from the cytosol to the plasma membrane, followed by a robust redistribution of beta-arrestin 2 and a profound change in cell morphology that occurs after 1 min of SPR stimulation. These data establish a role for GRKs and beta-arrestins in homologous desensitization of the SPR and provide the first visual and temporal resolution of the sequence of events underlying homologous desensitization of a GPCR in living cells.
 ...
PMID:Real-time visualization of the cellular redistribution of G protein-coupled receptor kinase 2 and beta-arrestin 2 during homologous desensitization of the substance P receptor. 1006 24

We used the Ca2+-sensitive fluorescent dye fura 2, together with measurements of intracellular D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], to assess the inhibitory effects of caffeine on signal transduction via G protein-coupled receptor pathways in isolated rat mandibular salivary acinar cells. ACh, norepinephrine (NE), and substance P (SP) all evoked substantial increases in the intracellular free Ca2+ concentration ([Ca2+]i). Responses to ACh and NE were markedly inhibited by prior application of 20 mM caffeine. The inhibitory effect of caffeine was not reproduced by phosphodiesterase inhibition with IBMX or addition of cell-permeant dibutyryl cAMP. In contrast to the ACh and NE responses, the [Ca2+]i response to SP was unaffected by caffeine. Despite this, SP and ACh appeared to mobilize Ca2+ from a common intracellular pool. Measurements of agonist-induced changes in Ins(1,4,5)P3 levels confirmed that caffeine inhibited the stimulus-response coupling pathway at a point before Ins(1,4,5)P3 generation. Caffeine did not, however, inhibit [Ca2+]i responses evoked by direct activation of G proteins with 40 mM F-. These data show that caffeine inhibits G protein-coupled signal transduction in these cells at some element that is common to the muscarinic and alpha-adrenergic signaling pathways but is not shared by the SP signaling pathway. We suggest that this element might be a specific structural motif on the G protein-coupled muscarinic and alpha-adrenergic receptors.
 ...
PMID:Caffeine does not inhibit substance P-evoked intracellular Ca2+ mobilization in rat salivary acinar cells. 1019 23

STKR is an insect G protein-coupled receptor, cloned from the stable fly Stomoxys calcitrans. It displays sequence similarity to vertebrate tachykinin [or neurokinin (NK)] receptors. Functional expression of the cloned STKR cDNA was obtained in cultured Drosophila melanogaster Schneider 2 (S2) cells. Insect tachykinin-like peptides or "insectatachykinins," such as Locusta tachykinin (Lom-TK) III, produced dose-dependent calcium responses in stably transfected S2-STKR cells. Vertebrate tachykinins (or neurokinins) did not evoke any effect at concentrations up to 10(-5) M, but an antagonist of mammalian neurokinin receptors, spantide II, inhibited the Lom-TK III-induced calcium response. Further analysis showed that the agonist-induced intracellular release of calcium ions was not affected by pretreatment of the cells with pertussis toxin. The calcium rise was blocked by the phospholipase C inhibitor U73122. In addition, Lom-TK III was shown to have a stimulatory effect on the accumulation of both inositol 1,4,5-trisphosphate and cyclic AMP. These are the same second messengers that are induced in mammalian neurokinin-dependent signaling processes.
 ...
PMID:Characterization of a receptor for insect tachykinin-like peptide agonists by functional expression in a stable Drosophila Schneider 2 cell line. 1080 Sep 64

Ligand-induced activation of G protein-coupled receptors is emerging as an important pathway leading to the activation of certain receptors with intrinsic tyrosine kinase activity, such as the epidermal growth factor receptor (EGFR). Substance P (SP) exerts many effects via activation of its G protein-coupled receptor (neurokinin-1, NK-1). SP participates in acute inflammation and activates key proteins involved in mitogenic pathways, such mitogen-activated protein kinases (MAPKs), stimulating DNA synthesis. We tested the hypothesis that SP-induced MAPK activation and DNA synthesis require activation of the EGFR. In U-373 MG cells, which express functional NK-1, SP induced tyrosine phosphorylation of several proteins including EGFR. SP induced formation of an activated EGFR complex containing the adapter proteins SHC and Grb2, but not c-Src. SP activated the MAPK pathway as shown by increased Erk2 kinase activity. SP induced Erk2 activation, and DNA synthesis was inhibited in cells transfected with a dominant negative EGFR plasmid lacking kinase activity, as well as in cells treated with a specific EGFR inhibitor. In addition, pertussis toxin, an inhibitor of Galpha(iota) protein subunits, prevented SP-induced EGFR transactivation and subsequent DNA synthesis. Our results implicate EGFR as an essential regulator in SP/NK-1-induced activation of the MAPK pathway and cell proliferation in U-373 MG cells, and these events are mediated by a pertussis toxin-sensitive Galpha protein. We suggest that this mechanism by which SP controls cell proliferation is an important pathway in tissue restoration and healing.
 ...
PMID:Epidermal growth factor receptor transactivation mediates substance P-induced mitogenic responses in U-373 MG cells. 1084 86

Substance P (SP) analogues including [d-Arg(1),d-Trp(5,7,9), Leu(11)]SP are broad spectrum neuropeptide antagonists and potential anticancer agents, but their mechanism of action is not fully understood. Here, we examined the mechanism of action of [d-Arg(1), d-Trp(5,7,9),Leu(11)]SP as an inhibitor of G protein-coupled receptor (GPCR)-mediated signal transduction and cellular DNA synthesis in Swiss 3T3 cells. Addition of [d-Arg(1),d-Trp(5,7,9), Leu(11)]SP, at 10 micrometer, caused a striking rightward shift in the dose-response curves of DNA synthesis induced by bombesin, bradykinin, or vasopressin and markedly inhibited the activation of p42(mapk) (ERK-2) and p44(mapk) (ERK-1) induced by these GPCR agonists. In addition, this SP analogue also prevented the protein kinase C-dependent activation of protein kinase D induced by these agonists. [d-Arg(1),d-Trp(5,7,9),Leu(11)]SP, at a concentration (10 micrometer) that inhibited these G(q)-mediated events, also prevented GPCR agonist-induced responses mediated through the G proteins of the G(12) subfamily. These include bombesin-induced assembly of focal adhesions, formation of parallel arrays of actin stress fibers, increase in the tyrosine phosphorylation of focal adhesion kinase (FAK), p130(Cas), and paxillin, and formation of a complex between FAK and Src. We conclude that [d-Arg(1),d-Trp(5,7,9),Leu(11)]SP acts as a mitogenic antagonist of neuropeptide GPCRs blocking signal transduction via both G(q) and G(12).
 ...
PMID:[D-Arg(1),D-Trp(5,7,9),Leu(11)]Substance P inhibits bombesin-induced mitogenic signal transduction mediated by both G(q) and G(12) in Swiss 3T3cells. 1088 May 15

Molecular models for the interaction of substance P (SP) with its G protein-coupled receptor, the neurokinin-1 receptor (NK-1R), have been developed. The ligand.receptor complex is based on experimental data from a series of photoaffinity labeling experiments and spectroscopic structural studies of extracellular domains of the NK-1R. Using the ligand/receptor contact points derived from incorporation of photolabile probes (p-benzoylphenylalanine (Bpa)) into SP at positions 3, 4, and 8 and molecular dynamics simulations, the topological arrangement of SP within the NK-1R is explored. The model incorporates the structural features, determined by high resolution NMR studies, of the second extracellular loop (EC2), containing contact points Met(174) and Met(181), providing important experimentally based conformational preferences for the simulations. Extensive molecular dynamics simulations were carried out to probe the nature of the two contact points identified for the Bpa(3)SP analogue (Bremer, A. A., Leeman, S. E., and Boyd, N. D. (2001) J. Biol. Chem. 276, 22857-22861), examining modes of ligand binding in which the contact points are fulfilled sequentially or simultaneously. The resulting ligand.receptor complex has the N terminus of SP projecting toward transmembrane helix (TM) 1 and TM2, exposed to the solvent. The C terminus of SP is located in proximity to TM5 and TM6, deeper into the central core of the receptor. The central portion of the ligand, adopting a helical loop conformation, is found to align with the helices of the central regions EC2 and EC3, forming important interactions with both of these extracellular domains. The model developed here allows for atomic insight into the biochemical data currently available and guides targeting of future experiments to probe specific ligand/receptor interactions and thereby furthers our understanding of the functioning of this important neuropeptide system.
 ...
PMID:Molecular characterization of the substance P*neurokinin-1 receptor complex: development of an experimentally based model. 1129 71

STKR is a G protein-coupled receptor that was cloned from the stable fly, Stomoxys calcitrans. Multiple sequence comparisons show that the amino acid sequence of this insect receptor displays several features that are typical for tachykinin (or neurokinin, NK) receptors. Insect tachykinin-related peptides, also referred to as "insectatachykinins," produce dose-dependent calcium responses in Drosophila melanogaster Schneider 2 cells, which are stably transfected with this receptor (S2-STKR). These responses do not depend on the presence of extracellular Ca(2+)-ions. A rapid agonist-induced increase of inositol 1,4,5-trisphosphate (IP(3)) is observed. This indicates that the agonist-induced cytosolic Ca(2+)-rise is caused by a release of Ca(2+) ions from intracellular calcium stores. The pharmacology of STKR is analyzed by studying the effects of the most important antagonists for mammalian NK-receptors on STKR-expressing insect cells. The results show that spantide II, a potent substance P antagonist, is a real antagonist of insectatachykinins on STKR. We have also tested the activity of a variety of natural insectatachykinin analogs by microscopic image analysis of calcium responses in S2-STKR cells. At a concentration of 1 microM, almost all natural analogs produce a significant calcium rise in stable S2-STKR cells. Interestingly, Stc-TK, an insectatachykinin that was recently discovered in the stable fly (S. calcitrans), also proved to be an STKR-agonist. Stc-TK, a potential physiological ligand for STKR, contains an Ala-residue (or A) instead of a highly conserved Gly-residue (or G). Arch.
 ...
PMID:Pharmacological characterization of STKR, an insect G protein-coupled receptor for tachykinin-like peptides. 1151 74

G protein-coupled receptor kinases (GRKs) phosphorylate agonist-occupied G protein-coupled receptors, leading to receptor desensitization. Seven GRKs, designated GRK1 through 7, have been characterized. GRK5 is negatively regulated by protein kinase C. We investigated whether human substance P receptor (hSPR) is a substrate of GRK5. We report that membrane-bound hSPR is phosphorylated by purified GRK5, and that both the rate and extent of phosphorylation increase dramatically in the presence of substance P. The phosphorylation has a high stoichiometry (20+/-4 mol phosphate/mol hSPR) and a low K(m) (1.7+/-0.1 nM). These data provide the first evidence that hSPR is a substrate of GRK5.
 ...
PMID:Human substance P receptor undergoes agonist-dependent phosphorylation by G protein-coupled receptor kinase 5 in vitro. 1206 42

The substance P/neurotachykinin-1 (NK-1) and the mu-opioid G protein-coupled receptor systems endow brainstem respiratory regions and display discrete developmental patterns. Hypoxia-induced neuropeptide release may increase receptor endocytosis, reducing receptor accessibility to ligands. We wondered whether the attenuated respiratory response to hypoxia of developing piglets after single (Respir. Physiol. 92 (1993a) 115) or repeated daily hypoxic exposure (J. Appl. Physiol. 83 (1997) 522) is influenced by differential endocytosis of NK-1 vs mu-opioid receptors. Whereas the long-term (24 h) response of both receptors to recurrent hypoxia in piglet brainstem is similar, i.e. upregulation, the short-term (5 min) response to single or recurrent hypoxia, albeit in rats, is different: radiolabelled NK-1 receptors are greatly reduced, suggesting enhanced endocytosis, but mu-opioid receptors remain unchanged, implying unaltered endocytosis. If confirmed in piglet brainstem, this difference would produce relatively more available mu-opioid receptors to opioid peptides in hypoxia that might contribute to the attenuated respiratory responses to single and repeated hypoxia during development.
 ...
PMID:Central neuropeptide systems and respiratory control during development. 1210 92


<< Previous 1 2 3 4 5 6 Next >>