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Tung Ming Fong - One of the best experts on this subject based on the ideXlab platform.
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Purification and reconstitution of a recombinant human Neurokinin-1 Receptor.
Journal of receptor and signal transduction research, 1996Co-Authors: Kathryn E. Mazina, Catherine D. Strader, Michael R. Tota, Selwyn Daniel, Tung Ming FongAbstract:AbstractRecombinant human Neurokinin-1 Receptors expressed in insect cells have been purified to near homogeneity by sequential metal-chelating chromatography and gel filtration chromatography. The purified Receptor consists of a single polypeptide with an apparent molecular weight of 50 kD as revealed by SDS gel electrophoresis, and exhibits a specific activity of 19 nmol of L-703,606 bound per mg of protein. Immunoblot experiments further confirm the identity of the stained protein band. The purified Receptor binds the antagonist L-703,606 with an affinity similar to that of native human Neurokinin-1 Receptor, and binds the agonist substance P with an affinity similar to that of the low affinity state of uncoupled native Receptor. The purified Receptor can be reconstituted with membranes from uninfected insect cells, and the reconstitution results in an increased affinity for substance P, consistent with the reappearance of the high affinity state of the Receptor for agonist in the presence of endogenou...
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Conformational compatibility as a basis of differential affinities of tachykinins for the Neurokinin-1 Receptor.
Biochemistry, 1995Co-Authors: Ruey-ruey C. Huang, Catherine D. Strader, Daniel Huang, Tung Ming FongAbstract:The Neurokinin-1 Receptor is characterized by sub-nanomolar affinity for substance P and 30-100 nM affinity for other substance P-related peptides, including Neurokinin B and septide. We have characterized a Neurokinin-1 Receptor mutant containing a Y216A substitution in the fifth transmembrane segment. This Receptor mutant binds substances P with sub-nanomolar affinity but loses much of its peptide discrimination capability, exhibiting 1-2 nM binding affinity for other tachykinins. Kinetic measurements of ligand binding indicate that the increased binding affinity of Neurokinin B and septide for the Y216A mutant compared to the wild-type Receptor is due to a 100-fold increase in the association rate constant without appreciable change in the dissociation rate constant. The substantially increased association rate constant for the Y216A mutant suggests that the mutant Receptor is probably more flexible in accommodating the approaching peptide molecule. It is proposed that a major determinant of peptide specificity for the wild-type Neurokinin-1 Receptor is the overall conformational compatibility between the Receptor and the ligand, rather than residue-specific interactions with the divergent N-terminal residues of different peptides. Furthermore, the highly conserved nature of Tyr-216 in the G protein coupled Receptor family suggests that this residue may also play an important role in the Receptor activation process in general.
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Interaction of glutamine 165 in the fourth transmembrane segment of the human Neurokinin-1 Receptor with quinuclidine antagonists.
The Journal of biological chemistry, 1994Co-Authors: Tung Ming Fong, Margaret A. Cascieri, Christopher John Swain, Dennis J. Underwood, Catherine D. StraderAbstract:Abstract Substance P binds to and activates the Neurokinin-1 Receptor with high affinity, thereby modulating several neuronal pathways including pain transmission and neurogenic inflammation. Several high affinity non-peptide antagonists have recently been described. To elucidate the molecular interactions specific for binding to the Neurokinin-1 Receptor, site-directed mutagenesis has been utilized to identify amino acid residues that interact directly with antagonists. Glutamine 165 in the fourth transmembrane segment was shown to be critical for the binding of CP-96,345 but not SR140333. Analysis of quinuclidine analogs suggests that glutamine 165 interacts with the C-3 heteroatom in this class of antagonists, probably through a hydrogen bond. Glutamine 165 also plays a minor role in the binding of peptides and RP67580. In contrast, serine 169 was determined to be critical for the binding of RP67580. These data indicate that residues 165 and 169 in the fourth transmembrane segment, along with residues in the fifth, sixth, and seventh transmembrane segments as demonstrated previously, form the non-peptide antagonist binding site in the Neurokinin-1 Receptor. Furthermore, the antagonist binding site overlaps with the binding site for peptide agonists in the fourth and seventh transmembrane segments.
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Interaction of substance P with the second and seventh transmembrane domains of the Neurokinin-1 Receptor
Biochemistry, 1994Co-Authors: Ruey-ruey C. Huang, Catherine D. Strader, Tung Ming FongAbstract:The Neurokinin-1 Receptor is a member of the G-protein-coupled Receptor family and has the highest affinity for the endogenous peptide transmitter substance P. Previous studies have indicated that several residues in the first and second extracellular segments, and at least part of the transmembrane domain, of the human Neurokinin-1 Receptor are involved in substance P binding to the Receptor. To further map the peptide binding site, single-residue substitutions in the transmembrane domains were analyzed. Asn-85, Asn-89, Tyr-92, and Asn-96 in the second transmembrane domain and Tyr-287 in the seventh transmembrane domain are required for the high-affinity binding of peptides, with Asn-85 possibly interacting with the C-terminus of substance P. In addition, Glu-78 in the second transmembrane domain and Tyr-205 in the fifth transmembrane domain appear to be involved in the Receptor activation process. Some of the key residues for peptide binding are likely to be near those residues that are required for the binding of competitive antagonists (such as His-197, His-265, and Tyr-287). These data suggest that a volume exclusion effect can explain the competitive antagonism of substance P binding by non-peptide antagonists. Furthermore, the key residues identified thus far are required for the high-affinity binding of all three Neurokinin peptides, consistent with a hypothesis that the conformational compatibility between the Receptor and the peptide agonist may be a major determinant of peptide recognition.
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The role of histidine 265 in antagonist binding to the Neurokinin-1 Receptor.
The Journal of biological chemistry, 1994Co-Authors: Tung Ming Fong, Margaret A. Cascieri, Christopher John Swain, Dennis J. Underwood, Catherine D. StraderAbstract:Previous studies suggested that the antagonist binding site in the Neurokinin-1 Receptor is composed of phylogenetically conserved residues, while phylogenetically divergent residues affect the conformation of the binding site. To test this hypothesis, we investigated the role of conserved residues in antagonist binding. Histidine 197 in the human Receptor was found to interact with CP-96,345 but not RP67580. In addition, a nearby residue, histidine 265 of the human Receptor, is required for the binding of RP67580 but not CP-96,345 or substance P. The interaction between residue 265 and RP67580 is consistent with a hydrogen bonding interaction. Analysis of several analogs of CP-96,345 revealed that histidine 265 of the human Receptor is in proximity to the substituted benzyl moiety of CP-96,345, and can interact with other analogs of CP-96,345. In contrast to the human Neurokinin-1 Receptor, both histidine 197 and histidine 265 in the rat Neurokinin-1 Receptor appear to interact with both CP-96,345 and RP67580. These results support a conformational difference between the antagonist binding sites of the rat and human Neurokinin-1 Receptors and provide a model for examining specific interactions between antagonists and the Receptor.
Catherine D. Strader - One of the best experts on this subject based on the ideXlab platform.
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Purification and reconstitution of a recombinant human Neurokinin-1 Receptor.
Journal of receptor and signal transduction research, 1996Co-Authors: Kathryn E. Mazina, Catherine D. Strader, Michael R. Tota, Selwyn Daniel, Tung Ming FongAbstract:AbstractRecombinant human Neurokinin-1 Receptors expressed in insect cells have been purified to near homogeneity by sequential metal-chelating chromatography and gel filtration chromatography. The purified Receptor consists of a single polypeptide with an apparent molecular weight of 50 kD as revealed by SDS gel electrophoresis, and exhibits a specific activity of 19 nmol of L-703,606 bound per mg of protein. Immunoblot experiments further confirm the identity of the stained protein band. The purified Receptor binds the antagonist L-703,606 with an affinity similar to that of native human Neurokinin-1 Receptor, and binds the agonist substance P with an affinity similar to that of the low affinity state of uncoupled native Receptor. The purified Receptor can be reconstituted with membranes from uninfected insect cells, and the reconstitution results in an increased affinity for substance P, consistent with the reappearance of the high affinity state of the Receptor for agonist in the presence of endogenou...
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Conformational compatibility as a basis of differential affinities of tachykinins for the Neurokinin-1 Receptor.
Biochemistry, 1995Co-Authors: Ruey-ruey C. Huang, Catherine D. Strader, Daniel Huang, Tung Ming FongAbstract:The Neurokinin-1 Receptor is characterized by sub-nanomolar affinity for substance P and 30-100 nM affinity for other substance P-related peptides, including Neurokinin B and septide. We have characterized a Neurokinin-1 Receptor mutant containing a Y216A substitution in the fifth transmembrane segment. This Receptor mutant binds substances P with sub-nanomolar affinity but loses much of its peptide discrimination capability, exhibiting 1-2 nM binding affinity for other tachykinins. Kinetic measurements of ligand binding indicate that the increased binding affinity of Neurokinin B and septide for the Y216A mutant compared to the wild-type Receptor is due to a 100-fold increase in the association rate constant without appreciable change in the dissociation rate constant. The substantially increased association rate constant for the Y216A mutant suggests that the mutant Receptor is probably more flexible in accommodating the approaching peptide molecule. It is proposed that a major determinant of peptide specificity for the wild-type Neurokinin-1 Receptor is the overall conformational compatibility between the Receptor and the ligand, rather than residue-specific interactions with the divergent N-terminal residues of different peptides. Furthermore, the highly conserved nature of Tyr-216 in the G protein coupled Receptor family suggests that this residue may also play an important role in the Receptor activation process in general.
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Interaction of glutamine 165 in the fourth transmembrane segment of the human Neurokinin-1 Receptor with quinuclidine antagonists.
The Journal of biological chemistry, 1994Co-Authors: Tung Ming Fong, Margaret A. Cascieri, Christopher John Swain, Dennis J. Underwood, Catherine D. StraderAbstract:Abstract Substance P binds to and activates the Neurokinin-1 Receptor with high affinity, thereby modulating several neuronal pathways including pain transmission and neurogenic inflammation. Several high affinity non-peptide antagonists have recently been described. To elucidate the molecular interactions specific for binding to the Neurokinin-1 Receptor, site-directed mutagenesis has been utilized to identify amino acid residues that interact directly with antagonists. Glutamine 165 in the fourth transmembrane segment was shown to be critical for the binding of CP-96,345 but not SR140333. Analysis of quinuclidine analogs suggests that glutamine 165 interacts with the C-3 heteroatom in this class of antagonists, probably through a hydrogen bond. Glutamine 165 also plays a minor role in the binding of peptides and RP67580. In contrast, serine 169 was determined to be critical for the binding of RP67580. These data indicate that residues 165 and 169 in the fourth transmembrane segment, along with residues in the fifth, sixth, and seventh transmembrane segments as demonstrated previously, form the non-peptide antagonist binding site in the Neurokinin-1 Receptor. Furthermore, the antagonist binding site overlaps with the binding site for peptide agonists in the fourth and seventh transmembrane segments.
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Interaction of substance P with the second and seventh transmembrane domains of the Neurokinin-1 Receptor
Biochemistry, 1994Co-Authors: Ruey-ruey C. Huang, Catherine D. Strader, Tung Ming FongAbstract:The Neurokinin-1 Receptor is a member of the G-protein-coupled Receptor family and has the highest affinity for the endogenous peptide transmitter substance P. Previous studies have indicated that several residues in the first and second extracellular segments, and at least part of the transmembrane domain, of the human Neurokinin-1 Receptor are involved in substance P binding to the Receptor. To further map the peptide binding site, single-residue substitutions in the transmembrane domains were analyzed. Asn-85, Asn-89, Tyr-92, and Asn-96 in the second transmembrane domain and Tyr-287 in the seventh transmembrane domain are required for the high-affinity binding of peptides, with Asn-85 possibly interacting with the C-terminus of substance P. In addition, Glu-78 in the second transmembrane domain and Tyr-205 in the fifth transmembrane domain appear to be involved in the Receptor activation process. Some of the key residues for peptide binding are likely to be near those residues that are required for the binding of competitive antagonists (such as His-197, His-265, and Tyr-287). These data suggest that a volume exclusion effect can explain the competitive antagonism of substance P binding by non-peptide antagonists. Furthermore, the key residues identified thus far are required for the high-affinity binding of all three Neurokinin peptides, consistent with a hypothesis that the conformational compatibility between the Receptor and the peptide agonist may be a major determinant of peptide recognition.
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The role of histidine 265 in antagonist binding to the Neurokinin-1 Receptor.
The Journal of biological chemistry, 1994Co-Authors: Tung Ming Fong, Margaret A. Cascieri, Christopher John Swain, Dennis J. Underwood, Catherine D. StraderAbstract:Previous studies suggested that the antagonist binding site in the Neurokinin-1 Receptor is composed of phylogenetically conserved residues, while phylogenetically divergent residues affect the conformation of the binding site. To test this hypothesis, we investigated the role of conserved residues in antagonist binding. Histidine 197 in the human Receptor was found to interact with CP-96,345 but not RP67580. In addition, a nearby residue, histidine 265 of the human Receptor, is required for the binding of RP67580 but not CP-96,345 or substance P. The interaction between residue 265 and RP67580 is consistent with a hydrogen bonding interaction. Analysis of several analogs of CP-96,345 revealed that histidine 265 of the human Receptor is in proximity to the substituted benzyl moiety of CP-96,345, and can interact with other analogs of CP-96,345. In contrast to the human Neurokinin-1 Receptor, both histidine 197 and histidine 265 in the rat Neurokinin-1 Receptor appear to interact with both CP-96,345 and RP67580. These results support a conformational difference between the antagonist binding sites of the rat and human Neurokinin-1 Receptors and provide a model for examining specific interactions between antagonists and the Receptor.
Jesus A. Angulo - One of the best experts on this subject based on the ideXlab platform.
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Methamphetamine induces striatal Neurokinin-1 Receptor endocytosis primarily in somatostatin/NPY/NOS interneurons and the role of dopamine Receptors in mice.
Synapse (New York N.Y.), 2010Co-Authors: Jing Wang, Jesus A. AnguloAbstract:Methamphetamine (METH) is a psychostimulant that induces long-term deficits of dopamine terminal markers and apoptotic cell death in the striatum. Our laboratory demonstrated that pharmacological blockade of the Neurokinin-1 Receptor attenuated the METH-induced damage to the striatal dopamine terminals and the apoptotic cell death of some striatal neurons. Here we employed histological methods to assess the effect of METH on Neurokinin-1 Receptor trafficking in the striatum as an indirect index of signaling by the neuropeptide substance P (natural ligand for this Receptor). Male mice received a single injection of METH (30 mg/kg, i.p.) and were sacrificed 30 minutes later. Immunohistofluorescence confocal microscopy confirmed that the Neurokinin-1 Receptor is located on cholinergic and somatostatin interneurons of the striatum. METH induced the trafficking of the Neurokinin-1 Receptor from the membrane into cytoplasmic endosomes primarily in the somatostatin/NPY/NOS interneurons and this phenomenon was attenuated by antagonists of the dopamine D1 (SCH-23390), D2 (raclopride) or Neurokinin-1 (WIN-51,708) Receptors. These data demonstrate that METH induces the trafficking of the striatal Neurokinin-1 Receptors principally in the somatostatin/NPY/NOS interneurons and that this phenomenon is dependent on the activity of dopamine D1 and D2 Receptors.
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Connection between the striatal Neurokinin-1 Receptor and nitric oxide formation during methamphetamine exposure.
Annals of the New York Academy of Sciences, 2008Co-Authors: Jing Wang, Syed F. Ali, Jesus A. AnguloAbstract:Methamphetamine (METH) is a widely used "club drug" that produces neural damage in the brain, including the loss of some neurons. METH-induced striatal neuronal loss has been attenuated by pretreatment with the Neurokinin-1 Receptor antagonist WIN-51,708 in mice. Using a histologic method, we have observed the internalization of the Neurokinin-1 Receptor into endosomes in the striatal somatostatin/NPY/nitric oxide synthase interneurons. To investigate the role of this interneuron in the striatal cell death induced by METH, we assessed by immunohistochemistry the number of striatal nitric oxide synthase-positive neurons in the presence of METH at 8 and 16 hours after systemic injection of a bolus of METH (30 mg/kg, i.p.). We found the number of striatal nitric oxide synthase-positive neurons unchanged at these time points after METH. In a separate experiment we measured the levels of striatal 3-nitrotyrosine (3-NT) by HPLC (high-pressure liquid chromatography) as an indirect index of nitric oxide synthesis. METH increased the levels of 3-nitrotyrosine in the striatum and this increase was significantly attenuated by pretreatment with a selective Neurokinin-1 Receptor antagonist. These observations suggest a causal relationship between the Neurokinin-1 Receptor and the activation of neuronal nitric oxide synthase that warrants further investigation.
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Neurokinin-1 Receptor antagonists block acute cocaine-induced horizontal locomotion.
Annals of the New York Academy of Sciences, 2006Co-Authors: Madelyne Kraft, Sonia Ahluwahlia, Jesus A. AnguloAbstract:Systemic exposure to Neurokinin-1 Receptor antagonists CP099994 or LY306740 prior to cocaine administration (10 mg/kg i.p.) blocks acute, cocaine-induced horizontal locomotion. CP099994 (30 mg/kg) was delivered i.p. 30 minutes before cocaine exposure, and LY306740 (5 mg/kg) was delivered continuously by osmotic minipump for 12-14 hours before cocaine administration. These results suggest that endogenous substance P acting via Neurokinin-1 Receptors is necessary for the expression of acute cocaine-induced hyperactivity.
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Ontogeny of Neurokinin‐1 Receptor Mediation of Methamphetamine Neurotoxicity in the Striatum of the Mouse Brain
Annals of the New York Academy of Sciences, 2006Co-Authors: Simone Allison, Dina Ibrahim, Jean Lud Cadet, Jesus A. AnguloAbstract:: We studied the role of the peptide substance P, signaling through the Neurokinin-1 (NK-1) Receptor, on methamphetamine-induced loss of dopamine transporter sites, a well-documented marker of toxicity in the striatum of the mouse brain, because this peptide is under dynamic regulation by the neurotransmitter dopamine. Methamphetamine is a psychostimulant that induces dopamine overflow from dopamine terminals of the striatum. Mice were given four injections of methamphetamine (7.5 mg/kg of body weight) at two-hour intervals and were sacrificed three days after the treatment. Dopamine transporter levels in the striatum were assessed by Receptor autoradiography with [125I]RTI-121. Exposure to methamphetamine resulted in significant loss of dopamine transporters in the caudate-putamen. This loss was prevented by preexposure (30 min before the first injection of methamphetamine) of the Neurokinin-1 Receptor antagonist L-733,060. The inactive enantiomer of L-733,060 (L-733,061) failed to protect dopamine transporter sites from methamphetamine, suggesting specificity for the Neurokinin-1 Receptor. Moreover, the protective effect of L-733,060 was observed in mice that were 10 weeks of age or older (dopamine transporter sites in mice six and eight weeks old were not protected from methamphetamine by the Neurokinin-1 Receptor antagonist). The results demonstrate that the deleterious effect of methamphetamine on dopamine transporter sites of the striatum is mediated via the Neurokinin-1 Receptor. The involvement of the NK-1 Receptor appears after the eighth week of postnatal life, suggesting that the link between dopamine transporters and the Neurokinin-1 Receptor becomes functional at approximately the time when the mouse reaches reproductive age.
Patrick M. Dougherty - One of the best experts on this subject based on the ideXlab platform.
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Sensory processing in the deep spinal dorsal horn of Neurokinin-1 Receptor knockout mice.
Anesthesiology, 2001Co-Authors: Han-rong Weng, Heikki Mansikka, Ronald Winchurch, Srinivasa N. Raja, Patrick M. DoughertyAbstract:Background The Neurokinin-1 Receptor and its primary ligand, substance P, are widely recognized as contributing to the spinal processing of nociceptive stimuli, yet the specific function of the Neurokinin-1 Receptor remains unclear. Methods To better clarify these functions, the authors examined the neurophysiologic responses of L4–L5 neurons in the deep dorsal horn to acute mechanical, thermal, and electrical stimuli in knockout and wild-type mice. In addition, the capacity of knockout and wild-type mice to show wind-up to repeated C-fiber stimuli and to show sensitization after cutaneous mustard oil was assessed. Results A total of 68 nociceptive neurons (35 in knockout, 33 in wild type) in laminae III–V were studied. No differences in the acute responses of neurons in knockout and wild-type mice to graded mechanical, thermal, or electrical stimuli or in the acute responses to mustard oil were observed. However, wind-up to repeated electrical stimulation at C-fiber intensity was significantly attenuated in the knockout mice compared with wild type controls. In addition, mustard oil–induced mechanical hypersensitivity was significantly reduced in the knockout mice. Conclusions These results indicate that Neurokinin-1 Receptors do not play a significant role in the responses of nociceptive neurons in the deep spinal dorsal horn to acute noxious mechanical, thermal, electrical, or chemical stimuli. On the other hand, Neurokinin-1 Receptors are critical for the central hyperexcitability that is observed in these neurons with repeated C-fiber inputs and to the central sensitization induced by topical mustard oil application.
Steven D. Douglas - One of the best experts on this subject based on the ideXlab platform.
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Neurokinin 1 Receptor signaling induces a pro inflammatory transcriptomic profile in cd16 monocytes
Journal of Neuroimmunology, 2021Co-Authors: Vasiliki Pappa, Steven D. Douglas, Sergei Spitsin, Peter J GaskillAbstract:Abstract Neurokinin-1 Receptor (NK1R) signaling can be immunomodulatory and it can lead to preferential transmigration of CD14 + CD16+ monocytes across the blood brain barrier, potentially promoting the development of inflammatory neurological diseases, such as neuroHIV. To evaluate how NK1R signaling alters monocyte biology, RNA sequencing was used to define NK1R-mediated transcriptional changes in different monocyte subsets. The data show that NK1R activation induces a greater number of changes in CD14 + CD16+ monocytes (152 differentially expressed genes), than in CD14+CD16− monocytes (36 genes), including increases in the expression of NF-κB and components of the NLRP3 inflammasome pathway. These results suggest that NK1R may alter the inflammatory state of CD14 + CD16+ monocytes, influencing the development of neuroinflammation.
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Substance P enhances HIV-1 infection in human fetal brain cell cultures expressing full-length Neurokinin-1 Receptor
Journal of NeuroVirology, 2013Co-Authors: Lynnae Schwartz, Steven D. Douglas, Florin Tuluc, Sergei V. Spitsin, John Meshki, John H. WolfeAbstract:The associations between the Neurokinin-1 Receptor (NK-1R), substance P (SP), and HIV-1 were investigated in neurosphere-derived cultures of microglial-depleted human fetal brain cells (HFBC). Full-length NK-1R was identified in HFBC cultures. SP treatment of the HFBC increased intracellular calcium mobilization and decreased electrical impedance, both of which were blocked by the NK-1R antagonist aprepitant. SP treatment of HIV-1-infected HFBC upregulated HIV-1 expression. These data show that human neural cells grown from neurospheres express functional full length NK-1R that is responsive to SP, and that SP enhanced HIV-1 infection in HBFC.
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Neurokinin 1 Receptor functional significance in the immune system in reference to selected infections and inflammation
Annals of the New York Academy of Sciences, 2011Co-Authors: Steven D. Douglas, Susan E. LeemanAbstract:The G protein-coupled Receptor (GPCR), Neurokinin-1 Receptor (NK1R), and its preferred ligand, substance P (SP), are reviewed in relationship to the immune system and selected infections. NK1R and SP are ubiquitous throughout the animal kingdom. This important pathway has unique functions in numerous cells and tissues. The interaction of SP with its preferred Receptor, NK1R, leads to the activation of nuclear factor-kappa B (NF-κB) and proinflammatory cytokines. NK1R has two isoforms, both a full-length and a truncated form. These isoforms have different functional significances and differ in cell signaling capability. The proinflammatory signals modulated by SP are important in bacterial, viral, fungal, and parasitic diseases, as well as in immune system function. The SP-NK1R system is a major class 1, rhodopsin-like GPCR ligand-Receptor interaction.
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Neurokinin 1 Receptor isoforms and the control of innate immunity
Trends in Immunology, 2009Co-Authors: Steven D. Douglas, Jian-ping Lai, Florin Tuluc, Laurie E. Kilpatrick, Dwight L EvansAbstract:Substance P is the prototype tachykinin peptide and triggers a variety of biological effects in both the nervous and immune system. Two naturally occurring variants of the Neurokinin 1 Receptor (NK1R) mediate the effects of SP: a ‘classic' full-length Receptor and a truncated (tail-less) form that lacks 96 amino acid residues at the C-terminus. Most research has focused on the full length Receptor and the truncated NK1R has not been extensively explored. Recent data demonstrate that truncated NK1R has important functional roles, including modulation of responses triggered by cytokines, chemotaxis of macrophages and regulation of HIV replication. Targeting the truncated NK1R with pharmacologic agents might result in novel therapeutic approaches in diseases which affect the immune system, including HIV disease.
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Neurokinin-1 Receptor Expression and Function in Human Macrophages and Brain
Annals of the New York Academy of Sciences, 2008Co-Authors: Steven D. Douglas, Jian-ping Lai, Florin Tuluc, Lynnae Schwartz, Laurie E. KilpatrickAbstract:Substance P (SP) is upregulated in HIV infection in adult men and women, as determined by increased plasma levels. There is a reciprocal and bidirectional relationship between substance P and HIV in HIV-infected monocyte-derived macrophages and cell lines (e.g., THP-1). Substance P up-regulates HIV and HIV up-regulates SP protein expression. Neurokinin-1 Receptor (NK1R) antagonists inhibit HIV infectivity through downregulation of the chemokine Receptor, CCR5, and downregulation of HIV LTR. Neurokinin-1 Receptor is expressed in full-length and truncated forms. The full-length NK1R is capable of signaling, whereas the truncated NK1 R primes the chemokine Receptor CCR5. Both full-length and truncated NK1R are expressed in several brain regions in human autopsy brains. SP-NK1R interactions have regulatory roles in inflammation and infection. The differential expression of truncated and full-length NK1R has important biological consequences. These include Receptor-Receptor interaction (e.g., NK1R-CCR5); changes in expression during cell differentiation (e.g., THP-1 cells); and differences in regional tissue distribution (e.g., differences in different brain regions). NK1R-SP Receptor pathways are important cell regulatory pathways.