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Quantifying Agonist Activity at G Protein-coupled Receptors
Published on: December 26, 2011
The human delta opioid receptor activates G(i1)alpha more efficiently than G(o1)alpha
H E Moon1, A Cavalli, D S Bahia
1Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK.
Journal of Neurochemistry
|March 22, 2001
Summary
The delta opioid receptor activates G(i1)alpha proteins more effectively than G(o1)alpha, influencing downstream signaling pathways. This finding is crucial for understanding opioid receptor pharmacology and drug development.
Area of Science:
- Pharmacology
- Molecular Biology
- Neuroscience
Background:
- The delta opioid receptor (DOR) mediates various physiological effects.
- Understanding its G protein coupling is key to its function.
- G(i1) and G(o1) are closely related G proteins often coupled to opioid receptors.
Purpose of the Study:
- To compare the relative capacities of the human delta opioid receptor to activate G(i1) and G(o1) alpha-subunits.
- To investigate the downstream signaling consequences of DOR activation via these G proteins.
Main Methods:
- Constructed fusion proteins linking pertussis toxin-insensitive G(i1)alpha or G(o1)alpha to the C-terminus of the human DOR.
- Expressed these fusion proteins in HEK 293 cells.
- Assessed receptor binding, adenylyl cyclase activity, and GTPase activity stimulated by D-ala(2),D-leu(5) enkephalin.
Main Results:
- Both fusion proteins bound the antagonist [(3)H]naltrindole with high affinity.
- D-ala(2),D-leu(5) enkephalin inhibited adenylyl cyclase activity in a pertussis toxin-insensitive manner.
- GTPase activity was stimulated by the agonist for both G proteins, but the GTP turnover number was over three times greater for G(i1)alpha compared to G(o1)alpha.
- This indicates more efficient receptor-promoted guanine nucleotide exchange and activation of G(i1)alpha.
Conclusions:
- The human delta opioid receptor exhibits a significantly higher capacity to activate G(i1)alpha compared to G(o1)alpha.
- Agonist occupation of DOR and MOR-1 equally efficiently couple to G(i1)alpha activation.
- These findings provide insights into the differential G protein coupling of opioid receptor subtypes.
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