Cannabinoid and kappa opioid receptors reduce potassium K current via activation of G(s) 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 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 GDPbetaS 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.
Hampson
R E
RE
Department of Physiology and Pharmacology, Wake Forest University, Winston Salem, North Carolina 27157, USA.
Mu
J
J
Deadwyler
S A
SA
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D000077285:Rimonabant; D015398:Signal Transduction / Q000502:physiology
D000700:Analgesics; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D017473:Receptors, Opioid, kappa; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019205:GTP-Binding Protein alpha Subunits, Gs; D000077285:Rimonabant; D011188:Potassium