The tachykinin NK1 receptor. Part I: Ligands and mechanisms of cellular activation

Quartara, Laura; Maggi, Carlo Alberto

doi:10.1016/s0143-4179(97)90001-9

Cited by 196 publications

(130 citation statements)

References 120 publications

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“…It is noteworthy that 0.1 nM is similar to the affinity of the NK 1 R for SP. 24 The morphology of NK 1 R-mediated cell death in 293T cells did not present features typical of apoptosis, but instead resembled the process of NK 1 R-mediated cell death observed in primary neurons. The cells rounded up but demonstrated no bleb formation, apoptotic body formation, cell shrinkage or nuclear fragmentation ( Figure 5A ± I).…”

Section: Nk 1 R Is a Death Receptor That Mediates Non-apoptotic Progrmentioning

confidence: 80%

“…Three apparently independent second messenger systems can be activated by G-proteins following ligand binding to NK 1 R: (1) Ca 2+ mobilization from both intra-and extracellular sources via stimulation of phospholipase C; (2) arachidonic acid mobilization via phospholipase A2; and (3) cAMP accumulation via stimulation of adenylate cyclase. 24 An alternative pathway, through interaction with b-arrestin, involves the activation of the MAPK pathway, leading to extracellular signal-regulated protein kinases 1 and 2 (ERKs) activation. 25 The development of specific agonists and antagonists for NK 1 R has supported a role for NK 1 R in numerous biological processes, such as the transmission of pain in the spinal cord.…”

Section: Introductionmentioning

confidence: 99%

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A ligand-receptor pair that triggers a non-apoptotic form of programmed cell death

et al. 2002

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Several receptors that mediate apoptosis have been identified, such as Fas and tumor necrosis factor receptor I. Studies of the signal transduction pathways utilized by these receptors have played an important role in the understanding of apoptosis. Here we report the first ligand-receptor pair ± the neuropeptide substance P and its receptor, neurokinin-1 receptor (NK 1 R) ± that mediates an alternative, non-apoptotic form of programmed cell death. This pair is widely distributed in the central and peripheral nervous systems, and has been implicated in pain mediation and depression, among other effects. Here we demonstrate that substance P induces a nonapoptotic form of programmed cell death in hippocampal, striatal, and cortical neurons. This cell death requires gene expression, displays a non-apoptotic morphology, and is independent of caspase activation. The same form of cell death is induced by substance P in NK 1 R-transfected human embryonic kidney cells. These results argue that NK 1 R activates a death pathway different than apoptosis, and provide a signal transduction system by which to study an alternative, non-apoptotic cell death program.

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Section: Nk 1 R Is a Death Receptor That Mediates Non-apoptotic Progrmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

A ligand-receptor pair that triggers a non-apoptotic form of programmed cell death

et al. 2002

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“…However, efforts to develop such therapies against tachykinin receptors such as NK1, 2 and 3 may be frustrated by the broad distribution and wide variety of functions known to be modulated by the tachykinin receptors. For example, tachykinin receptors are distributed widely throughout the body 82 and regulate a wide range of physiological processes including blood pressure, 83,84 emesis, 85 inflammation, 86 the immune response. 87 An alternative and promising approach to systemic drug therapy being currently explored involves the use of gene therapy.…”

Section: Discussionmentioning

confidence: 99%

A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P

et al. 2006

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The neuropeptide substance P (SP), encoded by the preprotachykinin-A (PPTA) gene, is expressed in the central and medial amygdaloid nucleus, where it plays a critical role in modulating fear and anxiety related behaviour. Determining the regulatory systems that support PPTA expression in the amygdala may provide important insights into the causes of depression and anxiety related disorders and will provide avenues for the development of novel therapies. In order to identify the tissue specific regulatory element responsible for supporting expression of the PPTA gene in the amygdala, we used long-range comparative genomics in combination with transgenic analysis and immunohistochemistry. By comparing human and chicken genomes, it was possible to detect and characterise a highly conserved long-range enhancer that supported tissue specific expression in SP expressing cells of the medial and central amygdaloid bodies (ECR1; 158.5 kb 5 0 of human PPTA ORF). Further bioinformatic analysis using the TRANSFAC database indicated that the ECR1 element contained multiple and highly conserved consensus binding sequences of transcription factors (TFs) such as MEIS1. The results of immunohistochemical analysis of transgenic lines were consistent with the hypothesis that the MEIS1 TF interacts with and maintains ECR1 activity in the central amygdala in vivo. The discovery of ECR1 and the in vivo functional relationship with MEIS1 inferred by our studies suggests a mechanism to the regulatory systems that control PPTA expression in the amygdala. Uncovering these mechanisms may play an important role in the future development of tissue specific therapies for the treatment of anxiety and depression.

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“…However, there is a Ôcross-talkÕ between tachykinins and their receptors (Saria 1999). Given that neostriatum and substantia nigra are particularly enriched in both SP and NK-3 receptors (Quartara and Maggi 1997;Saria 1999), the genetic ablation of NK-1 receptor may lead to compensatory alterations during development, such that SP may signal through NK-3 receptor. This is especially a concern in METH neurotoxicity as the neostriatum and substantia nigra are two major areas involved in the selective dopaminergic degeneration.…”

Section: Discussionmentioning

confidence: 99%

Neurokinin‐1 (NK‐1) receptor antagonists abrogate methamphetamine‐induced striatal dopaminergic neurotoxicity in the murine brain

Cadet

Angulo

2002

Journal of Neurochemistry

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Methamphetamine (METH) is an addictive substance that also causes extensive neural degeneration in the central nervous system. Because METH augments striatal substance P (SP) levels, we hypothesized that this neuropeptide plays a role in methamphetamine-induced toxicity and neural damage in the striatum. In this study we present evidence demonstrating that signaling through the neurokinin-1 (NK-1) receptor by SP plays an important role in methamphetamine-induced toxicity in the striatum. We tested the effects of the selective NK-1 receptor antagonists WIN-51,708 and L-733,060 on several markers of dopaminergic terminal toxicity in the mouse striatum. Administration of NK-1 receptor antagonist prevented the loss of dopamine transporters assessed by autoradiography and western blotting, the loss of tissue dopamine assessed by high-pressure liquid chromatography, and the loss of tyrosine hydroxylase, as well as the induction of glial fibrillary acidic protein determined by western blotting. Pre-treatment with NK-1 receptor antagonist had no effect on METH-induced hyperthermia. Pre-exposure of mice to either of the NK-1 receptor antagonists alone was without effect on all of these neurochemical markers. These results provide the first evidence that tachykinins, particularly SP, acting through NK-1 receptors, play a crucial role in the pathogenesis of nigrostriatal dopaminergic terminal degeneration induced by METH. This finding could lead to novel therapeutic strategies to offset drug addictions as well as in the treatment of a number of disorders including Parkinson's and Huntington's diseases.

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The tachykinin NK1 receptor. Part I: Ligands and mechanisms of cellular activation

Cited by 196 publications

References 120 publications

A ligand-receptor pair that triggers a non-apoptotic form of programmed cell death

A ligand-receptor pair that triggers a non-apoptotic form of programmed cell death

A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P

Neurokinin‐1 (NK‐1) receptor antagonists abrogate methamphetamine‐induced striatal dopaminergic neurotoxicity in the murine brain

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