Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling

Alexander Samoshkin, Marino Convertino, Chi T. Viet, Jeffrey S. Wieskopf, Oleg Kambur, Jaclyn Marcovitz, Pinkal Patel, Laura S. Stone, Eija Kalso, Jeffrey S. Mogil, Brian L. Schmidt, William Maixner, Nikolay Dokholyan, Luda Diatchenko

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The primary molecular target for clinically used opioids is the μ-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective β2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with β2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by β2-AR antagonists, providing a new avenue for opioid therapy.

Original languageEnglish (US)
Article number18198
JournalScientific reports
Volume5
DOIs
StatePublished - Dec 11 2015

Fingerprint

Opioid Receptors
Opioid Analgesics
Adrenergic Receptors
Ligands
Calcium
Adrenergic Antagonists
Hyperalgesia
Spinal Ganglia
Neuroblastoma
Analgesics
Rodentia
Protein Isoforms
Cell Membrane
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Samoshkin, A., Convertino, M., Viet, C. T., Wieskopf, J. S., Kambur, O., Marcovitz, J., ... Diatchenko, L. (2015). Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling. Scientific reports, 5, [18198]. https://doi.org/10.1038/srep18198
Samoshkin, Alexander ; Convertino, Marino ; Viet, Chi T. ; Wieskopf, Jeffrey S. ; Kambur, Oleg ; Marcovitz, Jaclyn ; Patel, Pinkal ; Stone, Laura S. ; Kalso, Eija ; Mogil, Jeffrey S. ; Schmidt, Brian L. ; Maixner, William ; Dokholyan, Nikolay ; Diatchenko, Luda. / Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling. In: Scientific reports. 2015 ; Vol. 5.
@article{a88e53a5c6ee4319949ce0d035eea494,
title = "Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling",
abstract = "The primary molecular target for clinically used opioids is the μ-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective β2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with β2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by β2-AR antagonists, providing a new avenue for opioid therapy.",
author = "Alexander Samoshkin and Marino Convertino and Viet, {Chi T.} and Wieskopf, {Jeffrey S.} and Oleg Kambur and Jaclyn Marcovitz and Pinkal Patel and Stone, {Laura S.} and Eija Kalso and Mogil, {Jeffrey S.} and Schmidt, {Brian L.} and William Maixner and Nikolay Dokholyan and Luda Diatchenko",
year = "2015",
month = "12",
day = "11",
doi = "10.1038/srep18198",
language = "English (US)",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

Samoshkin, A, Convertino, M, Viet, CT, Wieskopf, JS, Kambur, O, Marcovitz, J, Patel, P, Stone, LS, Kalso, E, Mogil, JS, Schmidt, BL, Maixner, W, Dokholyan, N & Diatchenko, L 2015, 'Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling', Scientific reports, vol. 5, 18198. https://doi.org/10.1038/srep18198

Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling. / Samoshkin, Alexander; Convertino, Marino; Viet, Chi T.; Wieskopf, Jeffrey S.; Kambur, Oleg; Marcovitz, Jaclyn; Patel, Pinkal; Stone, Laura S.; Kalso, Eija; Mogil, Jeffrey S.; Schmidt, Brian L.; Maixner, William; Dokholyan, Nikolay; Diatchenko, Luda.

In: Scientific reports, Vol. 5, 18198, 11.12.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling

AU - Samoshkin, Alexander

AU - Convertino, Marino

AU - Viet, Chi T.

AU - Wieskopf, Jeffrey S.

AU - Kambur, Oleg

AU - Marcovitz, Jaclyn

AU - Patel, Pinkal

AU - Stone, Laura S.

AU - Kalso, Eija

AU - Mogil, Jeffrey S.

AU - Schmidt, Brian L.

AU - Maixner, William

AU - Dokholyan, Nikolay

AU - Diatchenko, Luda

PY - 2015/12/11

Y1 - 2015/12/11

N2 - The primary molecular target for clinically used opioids is the μ-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective β2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with β2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by β2-AR antagonists, providing a new avenue for opioid therapy.

AB - The primary molecular target for clinically used opioids is the μ-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective β2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with β2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by β2-AR antagonists, providing a new avenue for opioid therapy.

UR - http://www.scopus.com/inward/record.url?scp=84949638591&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949638591&partnerID=8YFLogxK

U2 - 10.1038/srep18198

DO - 10.1038/srep18198

M3 - Article

VL - 5

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 18198

ER -