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 V. Dokholyan; Luda Diatchenko

doi:10.1038/srep18198

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 V. Dokholyan, Luda Diatchenko

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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 language	English (US)
Article number	18198
Journal	Scientific reports
Volume	5
DOIs	https://doi.org/10.1038/srep18198
State	Published - Dec 11 2015
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank Dr. Lefkowitz (Duke University Medical Center, Durham, NC, USA) for providing the HEK293 cell line stably expressing FLAG-β2-adrenoceptors. This work was supported in part by following grants: P01 NS045685 (LD, WM), STTR 1R41DA032293 (LD, NVD, WM) and R01DE019796 (BLS), Oral and Maxillofacial Surgery Research Support Grant (BLS, CTV), CERC09 (LD), the Louise and Alan Edwards Foundation (JSM), Pfizer Canada Professorship in Pain Research (LD), and T90 training grant 1T90DE021986 (AS). Imaging was supported by the Confocal and Multiphoton Imaging Core of NINDS Center Grant P30 NS045892.

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Samoshkin, A., Convertino, M., Viet, C. T., Wieskopf, J. S., Kambur, O., Marcovitz, J., Patel, P., Stone, L. S., Kalso, E., Mogil, J. S., Schmidt, B. L., Maixner, W., Dokholyan, N. V., & Diatchenko, L. (2015). Structural and functional interactions between six-transmembrane μ-opioid receptors and β₂-adrenoreceptors modulate opioid signaling. Scientific reports, 5, Article 18198. https://doi.org/10.1038/srep18198

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, NV & 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

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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 Dokholyan, {Nikolay V.} and Luda Diatchenko",

note = "Funding Information: We would like to thank Dr. Lefkowitz (Duke University Medical Center, Durham, NC, USA) for providing the HEK293 cell line stably expressing FLAG-β2-adrenoceptors. This work was supported in part by following grants: P01 NS045685 (LD, WM), STTR 1R41DA032293 (LD, NVD, WM) and R01DE019796 (BLS), Oral and Maxillofacial Surgery Research Support Grant (BLS, CTV), CERC09 (LD), the Louise and Alan Edwards Foundation (JSM), Pfizer Canada Professorship in Pain Research (LD), and T90 training grant 1T90DE021986 (AS). Imaging was supported by the Confocal and Multiphoton Imaging Core of NINDS Center Grant P30 NS045892.",

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doi = "10.1038/srep18198",

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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 V.

AU - Diatchenko, Luda

N1 - Funding Information: We would like to thank Dr. Lefkowitz (Duke University Medical Center, Durham, NC, USA) for providing the HEK293 cell line stably expressing FLAG-β2-adrenoceptors. This work was supported in part by following grants: P01 NS045685 (LD, WM), STTR 1R41DA032293 (LD, NVD, WM) and R01DE019796 (BLS), Oral and Maxillofacial Surgery Research Support Grant (BLS, CTV), CERC09 (LD), the Louise and Alan Edwards Foundation (JSM), Pfizer Canada Professorship in Pain Research (LD), and T90 training grant 1T90DE021986 (AS). Imaging was supported by the Confocal and Multiphoton Imaging Core of NINDS Center Grant P30 NS045892.

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.

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