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Journal of Neuroscience, Vol 14, 3842-3851, Copyright © 1994 by Society for Neuroscience
mu-Opioid receptor-mediated reduction of neuronal calcium current occurs via a G(o)-type GTP-binding protein
HC Moises, KI Rusin and RL Macdonald
Department of Physiology, University of Michigan, Ann Arbor 48109-0622.
It has recently been shown that the activation of mu-opioid receptors
inhibits several components of calcium channel current in rat DRG sensory
neurons. mu-Opioid receptors, acting through the pertussis toxin
(PTX)-sensitive substrate Gi, also reduce the activity of neuronal
adenylate cyclase, but the relationship of this effect to changes in
calcium channel activity has yet to be determined. Using whole-cell
recordings from acutely isolated rat DRG neurons, we examined the ability
of the mu-opioid-selective agonist Tyr-Pro-NMe-Phe- D-Pro-NH2 (PLO17) to
reduce calcium current after treatment with PTX and in the presence of the
nonhydrolyzable GTP analog guanosine 5'-[- thio]triphosphate (GTP gamma S),
to assess the role of G-proteins in the coupling of mu-opioid receptors to
calcium channels. Inhibition of current by PLO17 was mimicked or rendered
irreversible by intracellular administration of GTP gamma S, an activator
of G-proteins, and was blocked by pretreatment of neurons with PTX. In
contrast, when the catalytic subunit of cAMP-dependent protein kinase was
included in the recording pipette, calcium currents increased in magnitude
throughout the recording without attenuation of responses to PLO17. Thus,
the mu- opioid-induced inhibition of calcium current occurs through
activation of a Gi- or G(o)-type G-protein, but independent of changes in
adenylate cyclase activity. As a first step in identifying this G- protein,
we compared the ability of several antisera directed against specific
regions of Gi and G(o)alpha subunits to block the inhibition in current by
PLO17. Intracellular dialysis with an antiserum specific for G(o) (GC/2)
attenuated calcium current inhibition by PLO17 in five of six neurons by an
average of 75%. In contrast, there was no attenuation in the response to
PLO17 when neurons were dialyzed with an anti-Gi1 alpha/Gi2 alpha antiserum
(AS/7) or antibodies specific for alpha subunits of Gi proteins (Gi1/Gi2 or
Gi3) in an identical manner. These results suggest that in rat DRG neurons
mu-opioid receptors couple to calcium channels via the PTX-sensitive G(o)
subclass of GTP- binding proteins.
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