Action of beta-amyloid peptide₁₋₄₀ on I(HVA) and its modulation by ginkgolide B.
Whole-cell patch clamp recording was used to investigate the action of beta-amyloid peptide(1-40) (Abeta(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 Abeta(1-40) at concentrations of 0.01~30 mumol/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 Abeta(1-40) almost had no effect on I(HVA) (n=5, P>0.05). L-type calcium channel antagonist nifedipine abolished the increase of I(HVA)by Abeta(1-40). The increase of I(HVA) by Abeta(1-40) (1.0 mumol/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 Abeta(1-40). The results indicate that Abeta(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 Abeta(1-40).
Department of Physiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Lei
L
Chen
Chang-Jin
CJ
Liu
Ming
M
Tang
Ai
A
Li
Xin-Wu
XW
Hu
Ying
Y
Zhou
Jurgen
J
Hescheler
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D015220:Calcium Channels / Q000187:drug effects*; D046934:Ginkgolides / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D046934:Ginkgolides; D007783:Lactones; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C045856:ginkgolide B