title: Suppression of outward K⁺ currents by WIN55212-2 in rat retinal ganglion cells is independent of CB1/CB2 receptors.
abstract: Cannabinoid CB1 receptor (CB1R) signaling system is extensively distributed in the vertebrate retina. Activation of CB1Rs regulates a variety of functions of retinal neurons through modulating different ion channels. In the present work we studied effects of this receptor signaling on K(+) channels in retinal ganglion cells by patch-clamp techniques. The CB1R agonist WIN55212-2 (WIN) suppressed outward K(+) currents in acutely isolated rat retinal ganglion cells in a dose-dependent manner, with an IC50 of 4.7 μM. We further showed that WIN mainly suppressed the tetraethylammonium (TEA)-sensitive K(+) current component. While CB1Rs were expressed in rat retinal ganglion cells, the WIN effect on K(+) currents was not blocked by either AM251/SR141716, specific CB1R antagonists, or AM630, a selective CB2R antagonist. Consistently, cAMP-protein kinase A (PKA) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways were unlikely involved in the WIN-induced suppression of the K(+) currents because both PKA inhibitors H-89/Rp-cAMP and MAPK/ERK1/2 inhibitor U0126 failed to block the WIN effects. WIN-induced suppression of the K(+) currents was not observed when WIN was intracellularly applied. Furthermore, an endogenous ligand of the cannabinoid receptor anandamide, the specific CB1R agonist ACEA and the selective CB2R agonist CB65 also suppressed the K(+) currents, and the effects were not blocked by AM251/SR141716 or AM630 respectively. All these results suggest that the WIN-induced suppression of the outward K(+) currents in rat retinal ganglion cells, thereby regulating the cell excitability, were not through CB1R/CB2R signaling pathways.
authors.affiliation: Institutes of Brain Science, Institute of Neurobiology and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: C-Q
authors.initials: CQ
authors.lastname: Zhang
authors.forename: H-J
authors.initials: HJ
authors.lastname: Wu
authors.forename: S-Y
authors.initials: SY
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Yin
authors.forename: X-J
authors.initials: XJ
authors.lastname: Lu
authors.forename: Y
authors.initials: Y
authors.lastname: Miao
authors.forename: X-H
authors.initials: XH
authors.lastname: Wang
authors.forename: X-L
authors.initials: XL
authors.lastname: Yang
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D012160:Retina / Q000166:cytology; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D012235:Rhodamines / Q000493:pharmacokinetics; D014795:Visual Pathways / Q000187:drug effects / Q000502:physiology
chemical_list: D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D012235:Rhodamines; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000255:Adenosine Triphosphate; C027755:rhodamine isothiocyanate
keywords: 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene; 2-AG; 2-Arachidonoylglycerol; 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; 4-AP; 4-aminopyridine; AC; ACEA; AEA; BC; CB1 receptor; CB1/CB2 receptor agonist; CB1R; CB2 receptor; CB2R; CB65; DMSO; EGTA; ERK; FAAH; Gb; HEPES; MAPK; N-(2-Chloroethyl)-5Z, 8Z,11Z,14Z-eic osatetraenamide; N-Cyclohexyl-7-chloro-1-[2-(4-morpholinyl) ethyl]quinolin-4(1H)-one-3-carboxamide; PKA; RITC; TEA; TEA-sensitive K(+) current; U0126; WIN; WIN55212-2; adenylate cyclase; anandamide; bipolar cell; cannabinoid receptor; dimethyl sulfoxide; eCB; endocannabinoid; ethylene glycol-bis(β-aminoethyl ether) N,N,N′,N′-tetraacetic acid; extracellular signal-regulated kinase; fatty acid amide hydrolase; glybenclamide; mitogen-activated protein kinase; patch-clamp; protein kinase A; rhodamine-B-isothiocyanate; tetraethylammonium; Δ(9)-THC; Δ(9)-tetrahydrocannabinol