Grilli M, Raiteri L, Patti L, Parodi M, Robino F, Raiteri M, Marchi M
Section of Pharmacology and Toxicology, Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Br J Pharmacol. 2006 Nov;149(6):724-32. doi: 10.1038/sj.bjp.0706914. Epub 2006 Oct 3.
Two metabolites of tryptophan, 5-hydroxyindole and kynurenic acid (kynurenate) affect the function of alpha7 nicotinic acetylcholine receptors (nAChRs), as measured by electrophysiological and Ca2+ fluorescence techniques. To better understand the modulations by 5-hydroxyindole and kynurenate of the function of nAChR subtypes, we compared the effects of 5-hydroxyindole and kynurenate on the release of various transmitters evoked by nAChR activation.
The function of alpha7nAChRs located on glutamatergic terminals was investigated by monitoring the release of [3H]D-aspartate or of endogenous glutamate from neocortical synaptosomes. We also comparatively considered non-alpha7 release-enhancing nAChRs localized on hippocampal noradrenergic or cholinergic terminals, as well as on striatal dopaminergic terminals.
Epibatidine or nicotine, inactive on their own on basal release, enhanced [3H]D- aspartate and glutamate efflux in presence of 5-hydroxyindole. The release evoked by nicotine plus 5-hydroxyindole was abolished by methyllycaconitine or alpha-bungarotoxin. Presynaptic nAChRs mediating the release of [3H]noradrenaline ([3H]NA), [3H]dopamine ([3H]DA), or [3H]ACh were inhibited by 5-OHi. The alpha7nAChR-mediated release of [3H]D-aspartate was reduced by kynurenate at concentrations unable to affect the non-alpha7 receptor-mediated release of tritiated NA, DA or ACh.
(i) 5-hydroxyindole permits selective activation of alpha7nAChRs mediating glutamate release; (ii) kynurenate down-regulates the permissive role of 5-hydroxyindole on alpha7nAChR activation; (iii) the non-alpha7nAChRs mediating release of NA, DA or ACh can be inhibited by 5-hydroxyindole, but not by kynurenate. These findings suggest up the possibility of developing novel drugs able to modulate selectively the cholinergic-glutamatergic transmission.
色氨酸的两种代谢产物，5-羟吲哚和犬尿烯酸（犬尿酸盐）会影响α7烟碱型乙酰胆碱受体（nAChRs）的功能，这是通过电生理和Ca2+荧光技术测定得出的。为了更好地理解5-羟吲哚和犬尿酸盐对nAChR亚型功能的调节作用，我们比较了5-羟吲哚和犬尿酸盐对nAChR激活所诱发的各种递质释放的影响。
通过监测[3H]D-天冬氨酸或内源性谷氨酸从新皮质突触体中的释放，来研究位于谷氨酸能终末的α7nAChRs的功能。我们还比较性地研究了位于海马去甲肾上腺素能或胆碱能终末以及纹状体多巴胺能终末上的非α7释放增强型nAChRs。
依博加碱或尼古丁本身对基础释放无活性，但在5-羟吲哚存在时会增强[3H]D-天冬氨酸和谷氨酸的外流。尼古丁加5-羟吲哚所诱发的释放可被甲基牛扁亭或α-银环蛇毒素消除。介导[3H]去甲肾上腺素（[3H]NA）、[3H]多巴胺（[3H]DA）或[3H]乙酰胆碱释放的突触前nAChRs会被5-OHi抑制。犬尿酸盐在无法影响非α7受体介导的氚化NA、DA或ACh释放的浓度下，会降低α7nAChR介导的[3H]D-天冬氨酸释放。
（i）5-羟吲哚可选择性激活介导谷氨酸释放的α7nAChRs；（ii）犬尿酸盐下调5-羟吲哚对α7nAChR激活的允许作用；（iii）介导NA、DA或ACh释放的非α7nAChRs可被5-羟吲哚抑制，但不能被犬尿酸盐抑制。这些发现提示了开发能够选择性调节胆碱能-谷氨酸能传递的新型药物的可能性。
