Low-affinity sulfonylurea binding sites reside on neuronal cell bodies in the brain
Low-affinity sulfonylurea binding sites reside on neuronal cell bodies in the brain
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DOI：
10.1016/s0006-8993(96)01006-2
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发表时间：
1997-01-16
期刊：
影响因子：
2.9
通讯作者：
Levin, BE
中科院分区：
文献类型：
--
作者：
DunnMeynell, AA;Routh, VH;Levin, BE
抗糖尿病磺酰脲类药物与细胞体和神经元末梢上的ATP敏感性钾（K-atp）通道相关的位点结合，当葡萄糖浓度升高或存在磺酰脲类药物时，这些位点增加其放电率或递质释放。高亲和力的磺酰脲类结合位点集中在黑质（SN）等区域，其中葡萄糖和磺酰脲类增加GABA神经元的递质释放。但在下丘脑腹内侧核（VMN）等区域缺乏高亲和力位点，当葡萄糖升高时，许多神经元会增加其活动。在这里，我们评估了高和低亲和力的磺酰脲结合放射自显影与20 nM [H-3]格列本脲在存在或不存在的GPP（MI）P。神经毒素病变与6-羟基多巴胺（6-OHDA），5，7-二羟色胺（5，7-DHT）和鹅膏蕈氨酸被用来阐明细胞的位置的两个网站中的VMN，SN和蓝斑（LC）。在VMN中，25%的位点是低亲和力的。6-OHDA和5，7-DHT均不影响[3 H]格列本脲结合，而鹅膏蕈氨酸减少了VMN神经元的数量，消除了低亲和力，而不改变高亲和力结合。在细胞贴附补丁的孤立VMN神经元，10 mM葡萄糖和100 μ M格列本脲降低了开放的K-ATP通道的概率表明，低亲和力的结合位点驻留在这些神经元。在SN网状部，鹅膏蕈氨酸减少神经元的数量和高亲和力[H-3]格列本脲结合减少了20%，而6-OHDA没有影响。在黑质延髓部，6-OHDA和鹅膏蕈氨酸破坏内源性多巴胺神经元，并选择性地消融低亲和力结合。在LC中，6-OHDA破坏去甲肾上腺素神经元并消除低亲和力结合。这些数据表明，低亲和力的磺酰脲类结合位点驻留在VMN，SN多巴胺和LC去甲肾上腺素神经元细胞体的细胞体和高亲和力的网站可能是在SN中的GABA神经元的轴突末端。
The antidiabetic sulfonylurea drugs bind to sites associated with an ATP-sensitive potassium (K-atp) channel on cell bodies and terminals of neurons which increase their firing rates or transmitter release when glucose concentrations rise or sulfonylureas are present. High-affinity sulfonylurea binding sites are concentrated in areas such as the substantia nigra (SN) where glucose and sulfonylureas increase transmitter release from GABA neurons. But there is a paucity of high-affinity sites in areas such as the hypothalamic ventromedial nucleus (VMN) where many neurons increase their activity when glucose rises. Here we assessed both high- and low-affinity sulfonylurea binding autoradiographically with 20 nM [H-3]glyburide in the presence or absence of Gpp(MI)p. Neurotoxin lesions with 6-hydroxydopamine (6-OHDA), 5,7-dihydroxytryptamine (5,7-DHT) and ibotenic acid were used to elucidate the cellular location of the two sites in the VMN, SN and locus coeruleus (LC). In the VMN, 25% of the sites were of low affinity. Neither 6-OHDA nor 5,7-DHT affected [3H]glyburide binding, while ibotenic acid reduced the number of VMN neurons and abolished low-affinity without changing high-affinity binding. In cell-attached patches of isolated VMN neurons, both 10 mM glucose and 100 mu M glyburide decreased the open probability of the K-atp channel suggesting that the low-affinity binding site resides on these neurons. In the SN pars reticulata, ibotenic acid reduced the number of neurons and high-affinity [H-3]glyburide binding was decreased by 20%, while 6-OHDA had no effect. In the SN pars compacta, both 6-OHDA and ibotenic acid destroyed endogenous dopamine neurons and selectively ablated low-affinity binding. In the LC, 6-OHDA destroyed norepinephrine neurons and abolished low-affinity binding. These data suggest that low-affinity sulfonylurea binding sites reside on cell bodies of VMN, SN dopamine and LC norepinephrine neuron cell bodies and that high-affinity sites may be on axon terminals of GABA neurons in the SN.