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

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 Gi/o protein-linked to several cellular processes; however, the decrease in I Kwas 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 Gsproteins with cholera toxin (CTX) produced the same decrease in I K amplitude as WIN-2, and the latter was blocked in CTX-treated cells. Gs protein inhibition via GDPβS 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 Gs 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 Gs protein signaling pathway involving PKC.