Differential effects of isoquinolinesulfonamide protein kinase inhibitors on CA1 responses in hippocampal slices.
Differential effects of isoquinolinesulfonamide protein kinase inhibitors on CA1 responses in hippocampal slices.
复制标题
异喹啉磺酰胺蛋白激酶抑制剂对海马切片 CA1 反应的不同影响。
DOI：
10.1016/0306-4522(91)90061-r
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发表时间：
1991
期刊：
影响因子：
3.3
通讯作者：
Vallano,ML
中科院分区：
文献类型：
--
作者：
Leahy,JC;Vallano,ML
The effects of the isoquinolinesulfonamide protein kinase inhibitors l-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) andN-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004) on CA1 responses in hippocampal slices of the rat were examined to clarify their mode of action, and also to further define the role of Ca2+-dependent kinases in long-term potentiation. Initially, the inhibitory potencies of H-7 and HA1004 against both protein kinase C and type II Ca2+/cahmodulin-dependent kinase were examined in standardin vitrophosphorylation assays. The apparentKivalues of H-7 and HA1004 for protein kinase C were 9 and 57μ M, respectively. In contrast, theKivalues of H-7 and HA1004 for type II calcium/ calmodulin-dependent protein kinase were 156 and 13μ M, respectively. These results indicate that H-7 is a more effective inhibitor of protein kinase C, whereas HA1004 is a more effective inhibitor of type II calcium/calmodulin-dependent protein kinase. Following the induction of long-term potentiation, addition of 50μ M H-7 or HA1004 substantially increased the amplitude of the population spike in a control pathway, while producing no change or a slight increase in the spike amplitude in a previously potentiated long-term potentiation pathway. Moreover, H-7 (50 μ M), but not HA1004, produced multiple population spikes in both pathways. Addition of a higher concentration of H-7 (300 μ M) reduced the amplitude of the initial population spike but still produced multiple spikes. HA1004 (300μ M) typically produced effects similar to those observed with 50 μ M H-7, increasing the amplitude of the control population spike and producing multiple spike activity in both pathways. In contrast to the differential concentration-dependent effects of H-7 on the population spike responses, qualitatively similar effects were observed at both low (50 μ M) and high (300μ M) concentrations with regard to synaptic field responses. The initial slope of the population excitatory postsynaptic potential was significantly reduced by H-7, to a similar degree in both pathways. HA1004 produced a modest, but insignificant reduction in both pathways.These results, in conjunction with other reports, suggest that H-7 and HA1004 exert complex concentration-dependent effects which synchronously affect both excitatory and inhibitory synaptic transmission. We hypothesize that reduction of the population excitatory postsynaptic potential and spike (300 μ M H-7) is due to reduction of excitatory inputs, whereas enhancement of the population spike amplitude (50 μ M H-7) and the production of multiple spikes are due to the reduction of GABA-mediated inhibitory inputs. Moreover, the actions of these drugs on synaptic transmission were not affected by prior induction of long-term potentiation, except for the effects of 50μ M H-7 on the population spike amplitude. However, the lack of further potentiation of the population spike amplitude with 50μ M H-7 is consistent with recent reports suggesting that reduction of inhibitory mechanisms contributes to spike long-term potentiation. The results of the phosphorylation assays suggest that the electrophysiological alterations observed following addition of H-7 and HA1004 can be attributed to inhibition of protein kinase C. The biochemical studies also indicate the potential usefulness of HA1004 as a potent inhibitor of type II calcium/calmodulin-dependent protein kinase.
