A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes

Mai, Quynh N.; Shenoy, Priyank; Quach, Tim; Retamal, Jeffri S.; Gondin, Arisbel B.; Yeatman, Holly R.; Aurelio, Luigi; Conner, Joshua W.; Poole, Daniel P.; Canals, Meritxell; Nowell, Cameron J.; Graham, Bim; Davis, Thomas P.; Briddon, Stephen J.; Hill, Stephen J.; Porter, Christopher J.H.; Bunnett, Nigel W.; Halls, Michelle L.; Veldhuis, Nicholas A.

doi:10.1016/J.JBC.2021.100345

Role of the renin–angiotensin–aldosterone and kinin–kallikrein systems in the cardiovascular complications of COVID-19 and long COVID (2021)
Journal Article
Cooper, S. L., Boyle, E., Jefferson, S. R., Heslop, C. R. A., Mohan, P., Mohanraj, G. G. J., …Woolard, J. (2021). Role of the renin–angiotensin–aldosterone and kinin–kallikrein systems in the cardiovascular complications of COVID-19 and long COVID. International Journal of Molecular Sciences, 22(15), Article 8255. https://doi.org/10.3390/ijms22158255

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory foc... Read More about Role of the renin–angiotensin–aldosterone and kinin–kallikrein systems in the cardiovascular complications of COVID-19 and long COVID.

Probing the binding of interleukin-23 to individual receptor components and the IL-23 heteromeric receptor complex in living cells using NanoBRET (2021)
Journal Article
Lay, C. S., Bridges, A., Goulding, J., Briddon, S. J., Soloviev, Z., Craggs, P. D., & Hill, S. J. (2022). Probing the binding of interleukin-23 to individual receptor components and the IL-23 heteromeric receptor complex in living cells using NanoBRET. Cell Chemical Biology, 29(1), 19-29.e6. https://doi.org/10.1016/j.chembiol.2021.05.002

Interleukin-23 (IL-23) is a pro-inflammatory cytokine involved in the host defence against pathogens, but also implicated in the development of several autoimmune disorders. The IL- 23 receptor has become a key target for drug discovery but the exact... Read More about Probing the binding of interleukin-23 to individual receptor components and the IL-23 heteromeric receptor complex in living cells using NanoBRET.

Subtype selective fluorescent ligands based on ICI 118,551 to study the human β2‐adrenoceptor in CRISPR/Cas9 genome‐edited HEK293T cells at low expression levels (2021)
Journal Article
Kellam, B., White, C. W., Goulding, J., Mistry, S. J., Soave, M., Woolard, J., …Hill, S. J. (2021). Subtype selective fluorescent ligands based on ICI 118,551 to study the human β2‐adrenoceptor in CRISPR/Cas9 genome‐edited HEK293T cells at low expression levels. Pharmacology Research and Perspectives, 9(3), Article e00779. https://doi.org/10.1002/prp2.779

Fluorescent ligand technologies have proved to be powerful tools to improve our understanding of ligand-receptor interactions. Here we have characterized a small focused library of nine fluorescent ligands based on the highly selective β2-adrenocepto... Read More about Subtype selective fluorescent ligands based on ICI 118,551 to study the human β2‐adrenoceptor in CRISPR/Cas9 genome‐edited HEK293T cells at low expression levels.

Use of NanoBiT and NanoBRET to monitor fluorescent VEGF-A binding kinetics to VEGFR2/NRP1 heteromeric complexes in living cells (2021)
Journal Article
Peach, C. J., Kilpatrick, L. E., Woolard, J., & Hill, S. J. (2021). Use of NanoBiT and NanoBRET to monitor fluorescent VEGF-A binding kinetics to VEGFR2/NRP1 heteromeric complexes in living cells. British Journal of Pharmacology, 178(12), 2393-2411. https://doi.org/10.1111/bph.15426

Background and Purpose: VEGF‐A is a key mediator of angiogenesis, primarily signalling via VEGF receptor 2 (VEGFR2). Endothelial cells also express the co‐receptor neuropilin‐1 (NRP1) that potentiates VEGF‐A/VEGFR2 signalling. VEGFR2 and NRP1 had d... Read More about Use of NanoBiT and NanoBRET to monitor fluorescent VEGF-A binding kinetics to VEGFR2/NRP1 heteromeric complexes in living cells.

Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A1 Receptor in Living Cells (2021)
Journal Article
Comeo, E., Trinh, P., Nguyen, A. T., Nowell, C. J., Kindon, N. D., Soave, M., …Scammells, P. J. (2021). Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A1 Receptor in Living Cells. Journal of Medicinal Chemistry, 64(10), 6670-6695. https://doi.org/10.1021/acs.jmedchem.0c02067

The adenosine A1 receptor (A1AR) is a G-protein-coupled receptor (GPCR) that provides important therapeutic opportunities for a number of conditions including congestive heart failure, tachycardia, and neuropathic pain. The development of A1AR-select... Read More about Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A1 Receptor in Living Cells.

Efficient G protein coupling is not required for agonist?mediated internalization and membrane reorganization of the adenosine A 3 receptor (2021)
Journal Article
Stoddart, L. A., Kilpatrick, L. E., Corriden, R., Kellam, B., Briddon, S. J., & Hill, S. J. (2021). Efficient G protein coupling is not required for agonist?mediated internalization and membrane reorganization of the adenosine A 3 receptor. FASEB Journal, 35(4), Article e21211. https://doi.org/10.1096/fj.202001729rr

Organization of G protein-coupled receptors at the plasma membrane has been the focus of much recent attention. Advanced microscopy techniques have shown that these receptors can be localized to discrete microdomains and reorganization upon ligand ac... Read More about Efficient G protein coupling is not required for agonist?mediated internalization and membrane reorganization of the adenosine A 3 receptor.

The use of fluorescence correlation spectroscopy to monitor cell surface ?2?adrenoceptors at low expression levels in human embryonic stem cell?derived cardiomyocytes and fibroblasts (2021)
Journal Article
Goulding, J., Kondrashov, A., Mistry, S. J., Melarangi, T., Vo, N. T. N., Hoang, D. M., …Hill, S. J. (2021). The use of fluorescence correlation spectroscopy to monitor cell surface β2‐adrenoceptors at low expression levels in human embryonic stem cell‐derived cardiomyocytes and fibroblasts. FASEB Journal, 35(4), Article e21398. https://doi.org/10.1096/fj.202002268r

The importance of cell phenotype in determining the molecular mechanisms underlying ?2- adrenoceptor (?2AR) function has been noted previously when comparing responses in primary cells and recombinant model cell lines. Here, we have generated haploty... Read More about The use of fluorescence correlation spectroscopy to monitor cell surface ?2?adrenoceptors at low expression levels in human embryonic stem cell?derived cardiomyocytes and fibroblasts.

Detection of genome-edited and endogenously expressed G protein-coupled receptors (2021)
Journal Article
Soave, M., Stoddart, L. A., White, C. W., Kilpatrick, L. E., Goulding, J., Briddon, S. J., & Hill, S. J. (2021). Detection of genome-edited and endogenously expressed G protein-coupled receptors. FEBS Journal, 288(8), 2585-2601. https://doi.org/10.1111/febs.15729

© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and major targets for FDA-approved d... Read More about Detection of genome-edited and endogenously expressed G protein-coupled receptors.

Investigation of Receptor Heteromers Using NanoBRET Ligand Binding (2021)
Journal Article
Johnstone, E. K. M., See, H. B., Abhayawardana, R. S., Song, A., Rosengren, K. J., Hill, S. J., & Pfleger, K. D. G. (2021). Investigation of Receptor Heteromers Using NanoBRET Ligand Binding. International Journal of Molecular Sciences, 22(3), Article 1082. https://doi.org/10.3390/ijms22031082

Receptor heteromerization is the formation of a complex involving at least two different receptors with pharmacology that is distinct from that exhibited by its constituent receptor units. Detection of these complexes and monitoring their pharmacolog... Read More about Investigation of Receptor Heteromers Using NanoBRET Ligand Binding.

A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes (2021)
Journal Article
Mai, Q. N., Shenoy, P., Quach, T., Retamal, J. S., Gondin, A. B., Yeatman, H. R., …Veldhuis, N. A. (2021). A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes. Journal of Biological Chemistry, 296, Article 100345. https://doi.org/10.1016/J.JBC.2021.100345

G-protein-coupled receptors (GPCRs) are traditionally known for signaling at the plasma membrane, but they can also signal from endosomes after internalization to control important pathophysiological processes. In spinal neurons, sustained endosomal... Read More about A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes.

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