Mapping Substance P Binding Sites on the Neurokinin-1 Receptor Using Genetic Incorporation of a Photoreactive Amino Acid

Valentin-Hansen, Louise; Park, Minyoung; Huber, Thomas; Grunbeck, Amy; Naganathan, Saranga; Schwartz, Thue W.; Sakmar, Thomas P.

doi:10.1074/jbc.m113.527085

Cited by 54 publications

(39 citation statements)

References 49 publications

(82 reference statements)

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“…SP in conjunction with NMDA-receptor activation induces gene expression that facilitates synaptic changes that eventually lead to longlasting potentiation. SP shows preferential binding to the ligandbinding site of NK1 receptors (37). Binding of SP to NK1 receptors leads to activation of adenylyl cyclase, hydrolysis of phosphoinositides, mobilization of intracellular calcium ions, and activation of downstream effector molecules such as PKA, PKC, and MAPK (38), all of which have been associated with the expression of LTP (39).…”

Section: Discussionmentioning

confidence: 99%

Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2

Dasgupta

Baby

Krishna

et al. 2017

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

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The hippocampal area (CA) CA2 is important for social interaction and is innervated by Substance P (SP)-expressing supramammillary (SuM) nucleus neurons. SP exerts neuromodulatory effects on pain processing and central synaptic transmission. Here we provide evidence that SP can induce a slowly developing NMDA receptor- and protein synthesis-dependent potentiation of synaptic transmission that can be induced not only at entorhinal cortical (EC)-CA2 synapses but also at long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. In addition, SP-induced potentiation of SC-CA2 synapses transforms a short-term potentiation of EC-CA2 synaptic transmission into LTP, consistent with the synaptic tagging and capture hypothesis. Interestingly, this SP-induced potentiation and associative interaction between the EC and SC inputs of CA2 neurons is independent of the GABAergic system. In addition, CaMKIV and PKMζ play a critical role in the SP-induced effects on SC-CA2 and EC-CA2 synapses. Thus, afferents from SuM neurons are ideally situated to prime CA2 synapses for the formation of long-lasting plasticity and associativity.

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Section: Discussionmentioning

confidence: 99%

Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2

Dasgupta

Baby

Krishna

et al. 2017

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

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“…These finding suggest that all three receptors possess specific binding sites for both SP and QWF. Site directed mutagenesis studies of NK-1R demonstrated that amino acid residues 23–25 (NQF) in the receptor’s amino terminus along with H 108 (third transmembrane domain), F 268 (sixth transmembrane domain), Y 287 (7 th transmembrane domain) are important for binding substance P [56–58]. Furthermore, histidine at position 197 (H 197 ) in the fifth transmembrane helix of human NK-1R binds specifically to the non-peptide receptor antagonist CP 96345 to block SP action [59].…”

Section: Conclusion and Future Directionmentioning

confidence: 99%

Mas-Related G Protein Coupled Receptor-X2: A Potential New Target for Modulating Mast Cell-Mediated Allergic and Inflammatory Diseases

Ali

2016

J immuno Biol

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Mast cells (MCs) are tissue resident immune cells that are best known for their roles in allergic and inflammatory diseases. In addition to the high affinity IgE receptor (FcεRI), MCs express numerous G protein coupled receptors (GPCRs), which are the most common targets of drug therapy. Neurokinin 1 receptor (NK-1R) is expressed on MCs and contributes to IgE and non-IgE-mediated responses in mice. Although NK-1R antagonists are highly effective in modulating experimental allergic and inflammatory responses in mice they lack efficacy in humans. This article reviews recent findings that demonstrate that while neuropeptides (NPs) activate murine MCs via NK-1R and Mas related G protein coupled receptor B2 (MrgprB2), they activate human MCs via Mas-related G protein coupled receptor X2 (MRGPRX2). Interestingly, conventional NK-1R antagonists have off-target activity against mouse MrgprB2 but not human MRGPRX2. These findings suggest that the failure to translate studies with NK-1R antagonists from in vivo mouse studies to the clinic likely reflects their lack of effect on human MRGPRX2. A unique feature of MRGPRX2 that distinguishes it from other GPCRs is that it is activated by a diverse group of ligands that include; neuropeptides, cysteine proteases, antimicrobial peptides and cationic proteins released from activated eosinophils. Thus, the development of small molecule MRGPRX2-specific antagonists or neutralizing antibodies may provide new targets for the treatment of MC-mediated allergic and inflammatory diseases.

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“…Following a peripheral tissue injury, it was demonstrated that SP and SP C‐terminal fragments (i.e. SP 3–11 , SP 5–11 and SP 8–11 ) have an agonist effect on the NK1R (Maggi, ; Michael‐Titus, Blackburn, Connolly, Priestley, & Whelpton, ; Myöhänen, Venäläinen, Garcia‐Horsman, & Männistö, ; Valentin‐Hansen et al, ). We therefore suspect that NKA fragments may also play an essential role in nociception.…”

Section: Resultsmentioning

confidence: 99%

“…Following a peripheral tissue injury, it was demonstrated that SP and SP C-terminal fragments (i.e. SP [3][4][5][6][7][8][9][10][11] ) have an agonist effect on the NK1R (Maggi, 1995;Michael-Titus, Blackburn, Connolly, Priestley, & Whelpton, 1999;Myöhänen, Venäläinen, Garcia-Horsman, & Männistö, 2008;Valentin-Hansen et al, 2014).…”

Section: Detection Of Npk and Nka Peptide Fragmentsmentioning

confidence: 99%

Characterization of neuropeptide K processing in rat spinal cord S9 fractions using high‐resolution quadrupole–Orbitrap mass spectrometry

Salem

Nkambeu

Beaudry

2018

Biomedical Chromatography

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Tachykinins are a family of pronociceptive neuropeptides with a specific role in pain and inflammation. Several mechanisms regulate endogenous tachykinins levels, including the differential expression of protachykinin mRNA and the controlled secretion of tachykinin peptides from neurons. We suspect that proteolysis regulates extracellular neuropeptide K (NPK) and neurokinin A (NKA) concentrations and NPK is a precursor of NKA. Here, we provide evidence that proteolysis controls NPK and NKA levels in the spinal cord, leading to the formation of active C-terminal peptide fragments. Using high-resolution mass spectrometry, specific tachykinin fragments were identified and characterized. The metabolic stability in rat spinal cord fractions of NPK and NKA was very short, resulting in half-lives of 1.9 and 2.2 min respectively. Following the degradation of NPK, several C-terminal fragments were identified, including NPK , NKA, NKA , NKA , NKA and NKA , which conserve affinity for the neurokinin 2 receptor but also for the neurokinin 1 receptor. Interestingly, the same fragments were identified following the degradation of NKA. A specific proprotein convertases inhibitor was used and showed a significant reduction in the rate of formation of NKA, providing strong evidence that proprotein convertase is involved in C-terminal processing of NPK in the spinal cord, leading to the formation of NKA.

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Mapping Substance P Binding Sites on the Neurokinin-1 Receptor Using Genetic Incorporation of a Photoreactive Amino Acid

Cited by 54 publications

References 49 publications

Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2

Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2

Mas-Related G Protein Coupled Receptor-X2: A Potential New Target for Modulating Mast Cell-Mediated Allergic and Inflammatory Diseases

Characterization of neuropeptide K processing in rat spinal cord S9 fractions using high‐resolution quadrupole–Orbitrap mass spectrometry

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