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The Journal of General Physiology (1)
The Journal of neuroscience : the official journal of the Society for Neuroscience (1)
Paukert, Martin (2)
Babini, Elena (1)
Bergles, Dwight E. (1)
Gründer, Stefan (1)
Huang, Yanhua H. (1)
Pusch, Michael (1)
Rothstein, Jeffrey D. (1)
Tanaka, Kohichi (1)
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Zones of Enhanced Glutamate Release from Climbing Fibers in the Mammalian Cerebellum
Huang, Yanhua H.
Rothstein, Jeffrey D.
Bergles, Dwight E.
The Journal of neuroscience : the official journal of the Society for Neuroscience
Purkinje cells in the mammalian cerebellum are remarkably homogeneous in shape and orientation, yet they exhibit regional differences in gene expression. Purkinje cells that express high levels of zebrin II (aldolase C) and the glutamate transporter EAAT4, cluster in parasagittal zones that receive input from distinct groups of climbing fibers (CFs); however, the physiological properties of CFs that target these molecularly distinct Purkinje cells have not been determined. Here we report that CFs that innervate Purkinje cells in zebrin II immunoreactive (Z+) zones release more glutamate per action potential than CFs in Z− zones. CF terminals in Z+ zones had larger pools of release-ready vesicles, exhibited enhanced multivesicular release, and produced larger glutamate transients. As a result, CF-mediated excitatory postsynaptic currents (EPSCs) in Purkinje cells decayed more slowly in Z+ zones, which triggered longer duration complex spikes containing a greater number of spikelets. The differences in the duration of CF EPSCs between Z+ and Z− zones persisted in EAAT4 knockout mice, indicating that EAAT4 is not required for maintaining this aspect of CF function. These results indicate that the organization of the cerebellum into discrete longitudinal zones is defined not only by molecular phenotype of Purkinje cells within zones, but also by the physiological properties of CFs that project to these distinct regions. The enhanced release of glutamate from CFs in Z+ zones may alter the threshold for synaptic plasticity and prolong inhibition of cerebellar output neurons in deep cerebellar nuclei.
Identification of the Ca2+ Blocking Site of Acid-sensing Ion Channel (ASIC) 1
The Journal of General Physiology
Acid-sensing ion channels ASIC1a and ASIC1b are ligand-gated ion channels that are activated by H+ in the physiological range of pH. The apparent affinity for H+ of ASIC1a and 1b is modulated by extracellular Ca2+ through a competition between Ca2+ and H+. Here we show that, in addition to modulating the apparent H+ affinity, Ca2+ blocks ASIC1a in the open state (IC50 ∼ 3.9 mM at pH 5.5), whereas ASIC1b is blocked with reduced affinity (IC50 > 10 mM at pH 4.7). Moreover, we report the identification of the site that mediates this open channel block by Ca2+. ASICs have two transmembrane domains. The second transmembrane domain M2 has been shown to form the ion pore of the related epithelial Na+ channel. Conserved topology and high homology in M2 suggests that M2 forms the ion pore also of ASICs. Combined substitution of an aspartate and a glutamate residue at the beginning of M2 completely abolished block by Ca2+ of ASIC1a, showing that these two amino acids (E425 and D432) are crucial for Ca2+ block. It has previously been suggested that relief of Ca2+ block opens ASIC3 channels. However, substitutions of E425 or D432 individually or in combination did not open channels constitutively and did not abolish gating by H+ and modulation of H+ affinity by Ca2+. These results show that channel block by Ca2+ and H+ gating are not intrinsically linked.
epithelial Na+ channel; ion channel; channel pore; Xenopus oocyte; channel gating
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