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The Journal of Neurophysiology Vol. 84 No. 5 November 2000, pp. 2356-2364
Copyright ©2000 by the American Physiological Society
Department of Physiology and Pharmacology, Wake Forest University, Winston Salem, North Carolina 27157
Hampson, Robert E.,
Jian Mu, and
Sam A. Deadwyler.
Cannabinoid and Kappa Opioid Receptors Reduce Potassium K
Current via Activation of Gs Proteins in Cultured
Hippocampal Neurons. J. Neurophysiol. 84: 2356-2364, 2000. The current study showed that potassium K current
(IK), which is evoked at depolarizing
potentials between
30 and +40 mV in cultured hippocampal neurons, was
significantly reduced by exposure to the CB1 cannabinoid receptor
agonist WIN 55,212-2 (WIN-2). WIN-2 (20-40 nM) produced an average
45% decrease in IK amplitude across
all voltage steps, which was prevented by SR141716A, the CB1 receptor
antagonist. The cannabinoid receptor has previously been shown to be
Gi/o protein-linked to several cellular
processes; however, the decrease in IK
was unaffected by modulators of Gi/o proteins and
agents that alter levels of protein kinase A. In contrast, CB1
receptor-mediated or direct activation of Gs
proteins with cholera toxin (CTX) produced the same decrease in
IK amplitude as WIN-2, and the latter
was blocked in CTX-treated cells. Gs protein
inhibition via GDP
S also eliminated the effects of WIN-2 on
IK. Consistent with this outcome,
activation of protein kinase C (PKC) by arachidonic acid produced
similar effects to WIN-2 and CTX. Kappa opioid receptor agonists, which also reduce IK amplitude via
Gs proteins, were compared with WIN-2 actions on
IK. The kappa receptor agonist U50,488
reduced IK amplitude in the same
manner as WIN-2, while the kappa receptor antagonist, nor-binaltorphimine, actually increased
IK amplitude and significantly reduced
the effect of co-administered WIN-2. The results indicate that CB1 and
kappa receptor activation is additive with respect to
IK amplitude, suggesting that CB1 and
kappa receptors share a common Gs protein
signaling pathway involving PKC.
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