Topographical distance between presynaptic Ca2+ channels and exocytotic Ca2+ sensors contributes to differential facilitatory actions of roscovitine on neurotransmitter release at cerebellar glutamatergic and GABAergic synapses
Topographical distance between presynaptic Ca2+ channels and exocytotic Ca2+ sensors contributes to differential facilitatory actions of roscovitine on neurotransmitter release at cerebellar glutamatergic and GABAergic synapses
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突触前 Ca2+ 通道和胞吐 Ca2+ 传感器之间的拓扑距离有助于 roscovitine 对小脑谷氨酸能和 GABA 能突触神经递质释放的不同促进作用
DOI：
10.1111/ejn.15487
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发表时间：
2021
影响因子：
3.4
通讯作者：
Konishi S.
中科院分区：
文献类型：
--
作者：
Satake S.;Konishi S.
钙通过电压门控 Ca2+ 通道流入突触前末梢，根据释放机制的特性触发神经递质的单泡或多泡释放。然而，多囊泡释放（MVR）的机制及其调控仍不清楚。先前的研究表明，在大鼠小脑中，细胞周期蛋白依赖性激酶抑制剂 roscovitine 通过增强谷氨酸的 MVR 来显着增加颗粒细胞 (GC)-浦肯野细胞 (PC) 突触的兴奋性突触后电流 (EPSC) 振幅。该化合物还可以通过 MVR 增强和 GABA 溢出，适度增强分子层中间神经元 (MLI)-PC 突触抑制性突触后电流 (IPSC) 的振幅并延长其衰减时间，从而持续激活突触周围 GABA 受体。 MVR 的增强可能取决于 Cav2.1 通道介导的 Ca2+ 内流的驱动力。为了确定突触前 Ca2+ 的不同时空动力学是否影响 MVR，我们比较了慢速和快速 Ca2+ 螯合剂（即 EGTA 和 BAPTA）对 roscovitine 诱导的 GC-PC 和 MLI-PC 突触作用的影响。膜渗透性 EGTA-AM 使 GC-PC EPSC 和 MLI-PC IPSC 振幅降低到类似程度，但抑制了 roscovitine 诱导的 EPSC 增强。相反，BAPTA-AM 减弱了 roscovitine 对 IPSC 的作用。这些结果表明，roscovitine 通过激活位于 Cav2.1 通道簇远端的释放机制来增强谷氨酸释放，同时以不太依赖于远端位点的方式增强 GABA 释放。因此，Ca2+通道、缓冲器和传感器之间的空间关系是roscovitine对小脑皮质中谷氨酸能和GABA能突触的差异促进作用的关键决定因素。
Calcium influx into presynaptic terminals through voltage‐gated Ca2+channels triggers univesicular or multivesicular release of neurotransmitters depending on the characteristics of the release machinery. However, the mechanisms underlying multivesicular release (MVR) and its regulation remain unclear. Previous studies showed that in rat cerebellum, the cyclin‐dependent kinase inhibitor roscovitine profoundly increases excitatory postsynaptic current (EPSC) amplitudes at granule cell (GC)‐Purkinje cell (PC) synapses by enhancing the MVR of glutamate. This compound can also moderately augment the amplitude and prolong the decay time of inhibitory postsynaptic currents (IPSCs) at molecular layer interneuron (MLI)‐PC synapses via MVR enhancement and GABA spillover, thus allowing for persistent activation of perisynaptic GABA receptors. The enhanced MVR may depend on the driving force for Cav2.1 channel‐mediated Ca2+influx. To determine whether the distinct spatiotemporal dynamics of presynaptic Ca2+influence MVR, we compared the effects of slow and fast Ca2+chelators, that is, EGTA and BAPTA, respectively, on roscovitine‐induced actions at GC‐PC and MLI‐PC synapses. Membrane‐permeable EGTA‐AM decreased GC‐PC EPSC and MLI‐PC IPSC amplitudes to a similar extent but suppressed the roscovitine‐induced enhancement of EPSCs. In contrast, BAPTA‐AM attenuated the effects of roscovitine on IPSCs. These results suggest that roscovitine augmented glutamate release by activating the release machinery located distally from the Cav2.1 channel clusters, while it enhanced GABA release in a manner less dependent on those at distal sites. Therefore, the spatial relationships among Ca2+channels, buffers, and sensors are critical determinants of the differential facilitatory actions of roscovitine on glutamatergic and GABAergic synapses in the cerebellar cortex.
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