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Vol. 286, Issue 1, 282-288, July 1998
Departments of
Pharmacology (A.A., F.M., J.R.T., J.H.W.),
Biological Chemistry (F.M.),
Psychology (J.H.W.), and
Mental Health
Research Institute (A.M., H.A.) University of Michigan, Ann Arbor,
Michigan
The ability of endogenous opioids to activate G proteins was measured
in membranes from C6 rat glioma cells stably expressing a
cloned rat mu receptor. Peptides representing each of
the three known families of endogenous opioids (enkephalins, endorphins and dynorphins) were studied, as well as two recently discovered endogenous opioids, endomorphin-1 and -2, which are thought to represent a fourth family of endogenous opioid peptides. Stimulation of
guanosine-5'-O-(3-[35S]thio)triphosphate
([35S]GTP
S) binding to membranes was used as a measure
of G protein activation. It was possible to differentiate high efficacy
compounds such as Tyr-D-Ala-Gly-(Me)Phe-Gly-ol from
lower-efficacy agonists such as morphine or meperidine. Met- and
leu-enkephalin, beta endorphin and dynorphin A were all
found to have high efficacy at the mu receptor, as were the
peptide fragments beta endorphin-(1-27) and dynorphin
A-(1-13). Endomorphin-1 and -2 were found to be partial agonists,
capable of both stimulating [35S]GTPS binding and
antagonizing the stimulation produced by the higher-efficacy agonist
Tyr-D-Ala-Gly-(Me)Phe-Gly-ol. Binding affinities for the
opioid agonists at the cloned mu receptor were measured
by the displacement of radiolabeled antagonist. It was found that the
Ki values closely matched the
EC50 values for [35S]GTPS binding
stimulation, indicating that a large receptor reserve does not exist
for the complete activation of G proteins in this system.
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