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PLoS One. 2015 Nov 10;10(11):e0142826. doi: 10.1371/journal.pone.0142826. eCollection 2015.

Differential Regulation of 6- and 7-Transmembrane Helix Variants of μ-Opioid Receptor in Response to Morphine Stimulation.

Author information

1
Biochemistry and Biophysics Department, University of North Carolina, 120 Mason Farm Road, Chapel Hill, NC, United States of America, 27599.
2
Alan Edwards Centre for Research on Pain, McGill University, 740 Dr. Penfield Avenue, Montreal, Quebec, Canada, H3A 0G1.
3
Bluestone Center for Clinic Research, New York University, New York, NY, United States of America, 10010.
4
Center for Pain Research and Innovation, University of North Carolina, 385 S. Columbia Street, Chapel Hill, NC, United States of America, 27599.
5
Department of Physiology and Cell Information Systems, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 0B1.

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 6TM-mOR-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.

PMID:
26554831
PMCID:
PMC4640872
DOI:
10.1371/journal.pone.0142826
[Indexed for MEDLINE]
Free PMC Article

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