Welsby Philip J, Rowan Michael J, Anwyl Roger
Department of Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland.
Eur J Neurosci. 2009 Jan;29(1):65-75. doi: 10.1111/j.1460-9568.2008.06562.x. Epub 2008 Dec 11.
We have previously shown that activation of nicotinic acetylcholine receptors (nAChRs) enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of alpha7 nAChR. In the present studies, mechanisms underlying the acute and chronic nicotinic enhancement of LTP were examined. In particular, the involvement of activation of intracellular kinases was examined using selective kinase antagonists, and the effects of enhancing cholinergic function with positive allosteric modulators of the alpha7 nAChR and with acetylcholinesterase (AChE) inhibitors were also investigated. Activation of extracellular signal-regulated kinase (ERK) and cAMP-dependent protein kinase (PKA) was found to be involved in the induction of the acute nicotinic enhancement of LTP, although not control LTP. In contrast, activation of the tyrosine kinase Src, Ca(2+)-calmodulin-dependent protein kinase II, Janus kinase 2 and p38 mitogen-activated protein kinase was not involved in the acute nicotinic enhancement of LTP, although Src activation was necessary for control LTP. Moreover, activation of phosphoinositide 3-kinase was involved in the acute nicotinic enhancement of LTP to a much lesser extent than in control LTP. Chronic nicotine enhancement of LTP was found to be dependent on PKA, ERK and Src kinases. Acute nicotinic enhancement of LTP was occluded by chronic nicotine treatment. The positive allosteric modulator PNU-120596 was found to strongly reduce the threshold for nicotinic enhancement of LTP, an affect mediated via the alpha7 nAChR as it was blocked by the selective antagonist methyllycaconitine. The AChE inhibitors tacrine and physostigmine enhanced control LTP.
我们之前已经表明，烟碱型乙酰胆碱受体（nAChRs）的激活通过α7 nAChR的激活在体外增强了大鼠齿状回的长时程增强（LTP）。在本研究中，我们研究了急性和慢性烟碱增强LTP的潜在机制。具体而言，我们使用选择性激酶拮抗剂研究了细胞内激酶激活的参与情况，并且还研究了用α7 nAChR的正变构调节剂和乙酰胆碱酯酶（AChE）抑制剂增强胆碱能功能的效果。我们发现，细胞外信号调节激酶（ERK）和cAMP依赖性蛋白激酶（PKA）的激活参与了LTP急性烟碱增强的诱导过程，尽管对对照LTP没有影响。相反，酪氨酸激酶Src、Ca（2+）-钙调蛋白依赖性蛋白激酶II、Janus激酶2和p38丝裂原活化蛋白激酶的激活不参与LTP的急性烟碱增强，尽管Src激活对于对照LTP是必需的。此外，磷脂酰肌醇3激酶的激活在LTP急性烟碱增强中的参与程度远低于对照LTP。我们发现，LTP的慢性尼古丁增强依赖于PKA、ERK和Src激酶。LTP的急性烟碱增强被慢性尼古丁处理所阻断。我们发现正变构调节剂PNU-120596强烈降低了LTP烟碱增强的阈值，这种作用是通过α7 nAChR介导的，因为它被选择性拮抗剂甲基lycaconitine所阻断。AChE抑制剂他克林和毒扁豆碱增强了对照LTP。
