Differential regulation of 6- and 7-Transmembrane helix variants of μ-opioid receptor in response to morphine stimulation

Marino Convertino, Alexander Samoshkin, Chi T. Viet, Josee Gauthier, Steven P.Li Fraine, Reza Sharif-Naeini, Brian L. Schmidt, William Maixner, Luda Diatchenko, Nikolay V. Dokholyan

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The pharmacological effect of opioids originates, at the cellular level, by their interaction with the μ-opioid receptor (mOR) resulting in the regulation of voltage-gated Ca2+ channels and inwardly rectifying K+ channels that ultimately modulate the synaptic transmission. Recently, an alternative six trans-membrane helix isoform of mOR, (6TM-mOR) has been identified, but its function and signaling are still largely unknown. Here, we present the structural and functional mechanisms of 6TM-mOR signaling activity upon binding to morphine. Our data suggest that despite the similarity of binding modes of the alternative 6TM-mOR and the dominant seven trans-membrane helix variant (7TM-mOR), the interaction with morphine generates different dynamic responses in the two receptors, thus, promoting the activation of different mOR-specific signaling pathways. We characterize a series of 6TMmOR- specific cellular responses, and observed that they are significantly different from those for 7TM-mOR. Morphine stimulation of 6TM-mOR does not promote a cellular cAMP response, while it increases the intracellular Ca2+ concentration and reduces the cellular K+ conductance. Our findings indicate that 6TM-mOR has a unique contribution to the cellular opioid responses. Therefore, it should be considered as a relevant target for the development of novel pharmacological tools and medical protocols involving the use of opioids.

Original languageEnglish (US)
Article numbere0142826
JournalPloS one
Volume10
Issue number11
DOIs
StatePublished - Nov 10 2015

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morphine
narcotics
Opioid Receptors
Morphine
Opioid Analgesics
receptors
Pharmacology
Inwardly Rectifying Potassium Channel
Membranes
calcium
Synaptic Transmission
synaptic transmission
Dynamic response
potassium channels
Protein Isoforms
Chemical activation
Electric potential

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Convertino, Marino ; Samoshkin, Alexander ; Viet, Chi T. ; Gauthier, Josee ; Fraine, Steven P.Li ; Sharif-Naeini, Reza ; Schmidt, Brian L. ; Maixner, William ; Diatchenko, Luda ; Dokholyan, Nikolay V. / Differential regulation of 6- and 7-Transmembrane helix variants of μ-opioid receptor in response to morphine stimulation. In: PloS one. 2015 ; Vol. 10, No. 11.
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Convertino, M, Samoshkin, A, Viet, CT, Gauthier, J, Fraine, SPL, Sharif-Naeini, R, Schmidt, BL, Maixner, W, Diatchenko, L & Dokholyan, NV 2015, 'Differential regulation of 6- and 7-Transmembrane helix variants of μ-opioid receptor in response to morphine stimulation', PloS one, vol. 10, no. 11, e0142826. https://doi.org/10.1371/journal.pone.0142826

Differential regulation of 6- and 7-Transmembrane helix variants of μ-opioid receptor in response to morphine stimulation. / Convertino, Marino; Samoshkin, Alexander; Viet, Chi T.; Gauthier, Josee; Fraine, Steven P.Li; Sharif-Naeini, Reza; Schmidt, Brian L.; Maixner, William; Diatchenko, Luda; Dokholyan, Nikolay V.

In: PloS one, Vol. 10, No. 11, e0142826, 10.11.2015.

Research output: Contribution to journalArticle

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AU - Dokholyan, Nikolay V.

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Convertino M, Samoshkin A, Viet CT, Gauthier J, Fraine SPL, Sharif-Naeini R et al. Differential regulation of 6- and 7-Transmembrane helix variants of μ-opioid receptor in response to morphine stimulation. PloS one. 2015 Nov 10;10(11). e0142826. https://doi.org/10.1371/journal.pone.0142826