Internalization of [3H]Substance P Analogues in NK-1 Receptor Transfected CHO Cells

Sagan, Sandrine; Lavielle, Solange

doi:10.1006/bbrc.2001.4687

Cited by 13 publications

(14 citation statements)

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“…Differences in the B max values were observed as well with a CHO clone expressing a lower level of NK-1 receptors in membrane homogenates prepared from the clone with the highest expression and in rat submandibular glands (7). Furthermore, the two binding sites internalize differently as observed with radiolabeled peptides (12). Altogether these results suggest that the differences in B max values for the two types of ligands cannot be explained by effects secondary to G-protein interactions.…”

mentioning

confidence: 64%

“…4 for a review). Binding experiments with SP analogs in tissues and in cells transfected with the NK-1 receptor have shown that two types of non-stoichiometric binding sites with distinct pharmacological profiles are associated with the NK-1 receptor (5)(6)(7)(8)(9)(10)(11)(12). In CHO cells, B max values for the two binding sites were found to be 6000 fmol/mg proteins and 800 fmol/mg proteins for the major binding site ( 11 ]SP-(7-11), respectively (7).…”

mentioning

confidence: 99%

“…In the CHO clone used herein, the more and less abundant binding sites represent 85 and 15% of the total population of receptors (6 pmol/mg of proteins), respectively (7). Substance P binds the two binding sites with high affinity, whereas some C-terminal fragment analogs of substance P and some substance P-(1-11) analogs, as well as the endogenous tachykinin NK-2 ligand neurokinin A, bind only the less abundant one (7)(8)(9)(10)(11)(12). Although several structure-activity relationship studies have been carried out, little is known about the differences in the molecular recognition of these two binding sites (8 -12).…”

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confidence: 99%

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Involvement of the Second Extracellular Loop (E2) of the Neurokinin-1 Receptor in the Binding of Substance P

Lequin

Bolbach

Frank

et al. 2002

Journal of Biological Chemistry

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Involvement of the Second Extracellular Loop (E2) of the Neurokinin-1 Receptor in the Binding of Substance P

Lequin

Bolbach

Frank

et al. 2002

Journal of Biological Chemistry

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“…A number of studies have shown two binding sites associated with the NK 1 receptor, leading to suggestions that these sites either represent two populations of receptors coupled to different G proteins (Holst et al, 2001) or represent two different molecular forms of the receptor (Alves et al, 2006). The major binding site on the NK 1 receptor has been termed the NK-1M site (Sagan and Lavielle, 2001). The less abundant binding site, termed NK-1m, is equivalent to the septide-sensitive binding site (Sagan et al, 1997), has a subnanomolar affinity for SP, and is coupled to PLC via G q .…”

Section: Discussionmentioning

confidence: 99%

“…Differences in desensitization and internalization of the NK-1m site have also been reported. Agonists at the NK-1m site do not produce maximal desensitization of the response to SP (Vigna, 2001), and internalization of the NK-1m site is temperature-independent (Sagan and Lavielle, 2001). In our hands, internalization of NK 1 receptors following either SP or RTKC is temperature-dependent, and both can produce maximal desensitization (Bennett et al, 2002;Perrine et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Functional Selectivity of NK₁Receptor Signaling: Peptide Agonists Can Preferentially Produce Receptor Activation or Desensitization

Simmons¹

2006

J Pharmacol Exp Ther

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A cascade of events follows binding of an agonist ligand to the tachykinin NK 1 receptor. These events include activation of multiple signal transduction pathways as well as cellular modulation of receptor function by the process of desensitization. This study examines the differences in the abilities of naturally occurring peptide agonist ligands of the tachykinin NK 1 receptor to preferentially direct signaling through the receptor to produce signal activation versus receptor desensitization. The differential effects of tachykinin peptides with respect to ligand competition binding, receptor-G protein coupling, intracellular Ca 2ϩ elevations, and receptor desensitization have been measured. In relation to its potency in competition binding studies, substance P produces desensitization at lower concentrations, whereas higher concentrations are required to elicit a Ca 2ϩ response. In contrast to this, a related peptide, ranatachykinin C, is more effective at activating a Ca 2ϩ response relative to its ability to produce desensitization. This difference in functional selectivity is conserved for an amphibian and two mammalian ortholog tachykinin receptors. The present study demonstrates that peptide agonist ligands of NK 1 receptors can preferentially produce signal activation or desensitization.Over the years, the interactions of ligands with receptors have been classified as agonist interactions or antagonist interactions. Recently, it has become clear that a multitude of effects can follow binding of a ligand to a receptor (Kenakin, 2002(Kenakin, , 2003. These effects involve activation of multiple signal transduction pathways as well as cellular modulation of receptor function.One way that receptor function is modulated is by the process of desensitization. Desensitization occurs when the response to an agonist wanes in the continued presence of that agonist. Studies from our lab (Perrine et al., 2000) and from other labs (Vigna, 2001) have shown that the ability of a tachykinin receptor agonist ligand to produce signal activation and its ability to produce desensitization are not necessarily correlated.Our initial findings in this area showed that four different tachykinin peptides, substance P (SP), ranatachykinin (RTK) A, RTKB, and RTKC, could each activate the signal transduction pathways of the bullfrog SP receptor. For SP and RTKA, the concentrations required to produce desensitization of the receptor were two to four times less than the concentrations required to produce receptor activation. In contrast to this, the concentrations of RTKB and RTKC that produced desensitization were two times greater than the concentration needed to activate the signal transduction pathway.These data suggested that agonist ligands of the NK 1 receptor may exhibit functional selectivity. That is, agonists with the highest affinity and efficacy to activate a given signal transduction pathway do not also show the greatest degree of desensitization. This possibility seems particularly conceivable with respect to pep...

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Targeting peptides and positron emission tomography

Lundqvist

Tolmachev

2002

Biopolymers

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Biologically active peptides have during the last decades made their way into conventional nuclear medicine diagnosis using single photon emission computed tomography (SPECT) and gamma-camera. Several clinical trails are also investigating the role of radiolabeled peptides for targeting radionuclide therapy. This has raised the question as to whether positron emission tomography (PET) can be used in order to obtain better quantitative information of the peptide distribution in tumor and healthy organs, i.e., to get a better dosimetry. Positron emitting analogs of the therapeutic radionuclides used have been produced and successfully applied in peptide pharmacokinetic measurements with PET. But the recent boom in (18)FDG-PET ((18)FDG = [(18)F]2-deoxy-2-fluoro-D-glucose), and with this a worldwide increasing number of PET systems, has also inspired several research groups to hunt for alternative labels to be used for peptide diagnostics and PET. The rapid kinetic of short peptides agrees well with the short half-lives of standard PET nuclides like (11)C and (18)F. Especially, (18)F appears to be excellent for labeling bioactive peptides due to its favorable physical and nuclear characteristics. However, with present techniques labeling peptides with (18)F is laborious and time-consuming, and is not yet a clinical alternative. Other halogens like (75, 76)Br and (124)I are, from the chemical point of view, easier to apply. But an even better labeling alternative may be positron emitting metal ions like (55)Co, (68)Ga, and (110m)In since they tend to give better intracellular retention and thus a better signal-to-background ratio than the halogen labels. The main drawback with these radionuclides is that they are not readily available. Some of these radionuclides also emit gamma in their decay that may affect the measuring properties of the PET equipment. This article reviews mainly the present situation of production and use of nonconventional positron emitters for peptide labeling.

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Internalization of [3H]Substance P Analogues in NK-1 Receptor Transfected CHO Cells

Cited by 13 publications

References 30 publications

Involvement of the Second Extracellular Loop (E2) of the Neurokinin-1 Receptor in the Binding of Substance P

Involvement of the Second Extracellular Loop (E2) of the Neurokinin-1 Receptor in the Binding of Substance P

Functional Selectivity of NK₁Receptor Signaling: Peptide Agonists Can Preferentially Produce Receptor Activation or Desensitization

Targeting peptides and positron emission tomography

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Internalization of [3H]Substance P Analogues in NK-1 Receptor Transfected CHO Cells

Cited by 13 publications

References 30 publications

Involvement of the Second Extracellular Loop (E2) of the Neurokinin-1 Receptor in the Binding of Substance P

Involvement of the Second Extracellular Loop (E2) of the Neurokinin-1 Receptor in the Binding of Substance P

Functional Selectivity of NK1Receptor Signaling: Peptide Agonists Can Preferentially Produce Receptor Activation or Desensitization

Targeting peptides and positron emission tomography

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Functional Selectivity of NK₁Receptor Signaling: Peptide Agonists Can Preferentially Produce Receptor Activation or Desensitization