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

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

ASJC Scopus subject areas

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

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  • Cite this

    Convertino, M., Samoshkin, A., Viet, C. T., Gauthier, J., Fraine, S. P. L., Sharif-Naeini, R., Schmidt, B. L., Maixner, W., Diatchenko, L., & Dokholyan, N. V. (2015). Differential regulation of 6- and 7-Transmembrane helix variants of μ-opioid receptor in response to morphine stimulation. PloS one, 10(11), [e0142826]. https://doi.org/10.1371/journal.pone.0142826