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Action of #beta#--amyloid peptide_(1-40) on I_(HVA) and its modulation by ginkgolide B

Chen Lei, Liu Changjin, Tang Ming, Li Ai, Hu Xinwu, Zhou Ying, JÜrgen Hescheler

Department of Physiology, Tongji Medical College, Huazhong University of Science and Technology. Wuhan 430030, China；Institute of Neurophysiology, University of Cologne, Cologne D-50931, Germany

Abstract

Whole-cell patch clamp recording was used to investigate the action of #beta#-amyloid peptide1-40 (A#beta#_(1-40)) on high voltage-activated calcium channel current (I_(HVA)) in acutely isolated hippocampal CA1 pyramidal neurons in rats and observe its modulation by ginkgolide B (GB). Drug was applied by extracellular bath or adding in the pipette solution, and its effect was determined by comparing the amplitude of (I_(HVA) before and after the drug application. Bath application of aggregated A#beta#_(1-40) at concentrations of 0.01--30 #mu#mol/L increased the amplitude of I_(HVA) in a dose-dependent manner by (5.43=3.01)% (n=8, P>0.05), (10.49±4.13)% (n=11, P>0.05), (40.69±8.01)% (n=16, P<0.01), (58.32±4.85)% (n=12, P<0.01), and (75.45±5.81)% (n=6, P<0.01), respectively, but had no effect on the I-V curve of I_(HVA); fresh A#beta#_(1-40) almost had no effect on I_(HVA) (n=5, P>0.05). L-type calcium channel antagonist nifedipine abolished the increase of IHVA by A#beta#_(1-40). The increase of I_(HVA) A#beta#_(1-40) (1.0 #mu#mol/L) was enhanced to (66.19±5.74)% (P<0.05) by 8-Br-cAMP (membrane permeable analogue of cAMP) and to (73.21±6.90)% (P<0.05) by forskolin, an adenylyl cyclase (AC) agonist, and reduced to (20.08±2.18)% (P<0.05) by H-89, cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) antagonist. GB effectively inhibited the increase of I_(HVA) by A#beta#_(1-40). The results indicate that A#beta#_(1-40) leads to an intracellular calcium overload by increasing I_(HVA) via AC-cAMP-PKA. This may be one of the mechanisms for its neurotoxicity. GB can prevent neurons from neurotoxicity by inhibiting abnormal calcium influx caused by A#beta#_(1-40).

Key words: Hippocampus;#beta#-amyloid peptide;Voltage-dependent calcium channel current;Ginkgolide B;Patch-clamp technique

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Citing This Article：

Chen Lei, Liu Changjin, Tang Ming, Li Ai, Hu Xinwu, Zhou Ying, JÜrgen Hescheler. Action of #beta#--amyloid peptide_(1-40) on I_(HVA) and its modulation by ginkgolide B . Acta Physiol Sin 2006; 58 (1): (in Chinese with English abstract).