Sulfonylurea-sensitive potassium current evoked by sodium-loading in rat midbrain dopamine neurons

被引:25
作者
Seutin, V
Shen, KZ
North, RA
Johnson, SW
机构
[1] OREGON HLTH SCI UNIV, VOLLUM INST, PORTLAND, OR 97201 USA
[2] OREGON HLTH SCI UNIV, DEPT PHYSIOL & PHARMACOL, PORTLAND, OR 97201 USA
[3] OREGON HLTH SCI UNIV, DEPT NEUROL, PORTLAND, OR 97201 USA
关键词
substantia nigra; ventral tegmental area; diazoxide; sodium pump; glibenclamide; tolbutamide;
D O I
10.1016/0306-4522(95)00489-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In Parkinson's disease, there is evidence of impaired mitochondrial function which reduces the capacity to synthesize ATP in dopamine neurons. This would be expected to reduce the activity of the sodium pump (Na+/K+ ATPase), causing increased intracellular levels of Na+. Patch pipettes were used to introduce Na+ (40 mM in pipette solutions) into dopamine neurons in the rat midbrain slice in order to study the electrophysiological effects of increased intracellular Na+. We found that intracellular Na+ loading evoked 100-300 pA of outward current (at -60 mV) and increased whole-cell conductance; these effects developed gradually during the first 10 min after rupture of the membrane patch. Extracellular Ba2+ reduced most of the outward current evoked by Na+ loading; this Ba2+-sensitive current reversed direction at the expected reversal potential for K+ (E(K)), and was also blocked by extracellular tetraethylammonium (30 mM) and intracellular Cs+ (which replaced K+ in pipette solutions). The sulfonylurea drugs glipizide (IC50 = 4.9 nM), tolbutamide (IC50 = 23 mu M) and glibenclamide (1 mu M) were as effective as 300 mu M Ba2+ in reducing the K+ current evoked by Na+ loading. When recording with ''control'' pipettes containing 15 mM Na+, diazoxide (300 mu M) increased chord conductance and evoked outward current at -60 mV, which also reversed direction near E(K). Effects of diazoxide were blocked by glibenclamide (1 mu M) or glipizide (300 nM). Diazoxide (300 mu M) and baclofen (3 mu M), which also evoked K+-mediated outward currents recorded with control pipettes, caused little additional increases in outward currents during Na+ loading. Raising ATP concentrations to 10 mM in pipette solutions failed to significantly reduce currents evoked by diazoxide or Na+ loading, suggesting that these currents may not be mediated by ATP-sensitive K+ channels. Finally, Na+ loading using pipettes containing Cs+ in place of K+ evoked a relatively small outward current (50-150 pA at -60 mV), which developed gradually over the first 10 min after rupturing the membrane patch. This current was reduced by dihydro-ouabain (3 mu M) and a low extracellular concentration of K+ (0.5 mM instead of 2.5 mM), but was not affected by Ba2+. We conclude that intracellular Na+ loading evokes a current generated by Na+/K+ ATPase in addition to sulfonylurea-sensitive K+ current. This Na+-dependent K+ current is unusual in its sensitivity to sulfonylureas, and could protect dopamine neurons against toxic effects of intracellular Na+ accumulation.
引用
收藏
页码:709 / 719
页数:11
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