The Journal of Neurophysiology Vol. 84 No. 5 November 2000, pp. 2356-2364
Copyright ©2000 by the American Physiological Society

Cannabinoid and Kappa Opioid Receptors Reduce Potassium K Current via Activation of G_s Proteins in Cultured Hippocampal Neurons

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 G_s Proteins in Cultured Hippocampal Neurons. J. Neurophysiol. 84: 2356-2364, 2000. The current study showed that potassium K current (I_K), 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 I_K amplitude across all voltage steps, which was prevented by SR141716A, the CB1 receptor antagonist. The cannabinoid receptor has previously been shown to be G_i/o protein-linked to several cellular processes; however, the decrease in I_K was unaffected by modulators of G_i/o proteins and agents that alter levels of protein kinase A. In contrast, CB1 receptor-mediated or direct activation of G_s proteins with cholera toxin (CTX) produced the same decrease in I_K amplitude as WIN-2, and the latter was blocked in CTX-treated cells. G_s protein inhibition via GDPS also eliminated the effects of WIN-2 on I_K. 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 I_K amplitude via G_s proteins, were compared with WIN-2 actions on I_K. The kappa receptor agonist U50,488 reduced I_K amplitude in the same manner as WIN-2, while the kappa receptor antagonist, nor-binaltorphimine, actually increased I_K 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 I_K amplitude, suggesting that CB1 and kappa receptors share a common G_s protein signaling pathway involving PKC.