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論文(リポジトリ) |
論文(リポジトリ)
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樋口, 宗史
概要:
It is an unsolved question how the neuron－specific genes are . regulated in the mature neurons. The neuronal regulation
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of neuropeptide Y （NPY） gene which is a cotransmitter of sympathetic neurons and expressed abundantly in the central nervous system. The regulation of this gene resembles that of tyrosine hydroxylase gene.Both the membrane depolarization induced by neural activity and neurotrophic factors such as NGF induced the transcriptiional activation of NPY and enkephalin genes. These mechanisms are due to both Ca/almodulin and MAPK （mitogen－activated protein kinase） dependent processes, respectively. These findings indicated that the transcriptional activations of neural genes are due to the novel transactivational mechanisms. The novel transcriptional factors will be reported.
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| 2.
論文(リポジトリ) |
論文(リポジトリ)
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三品, 昌美
概要:
The glutamate receptor channel plays a key role in brain function. Most of the fast excitatory synaptic transmission is
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mediated by glutamate receptor channels in the central nervous system. Furthermore, glutamate receptor channels are essential for activity-dependent synaptic plasticity such as long-term potentiation and long-term depression, which are thought to underlie memory acquisition and learning. Evidence is accumulating that glutamate receptor channels are involved in experience-dependent synaptic plasticity during development and degenerative brain disorders. We have identified more than a dozen subunits of the mouse glutamate receptor channel by molecular cloning. These glutamate receptor channel subunits possess four putative transmembrane segments characteristic for neurotransmitter-gated ion channels and have been classified into six subfamilies (α, β, γ, δ, ε and ζ subfamilies) according to the amino acid sequence homology. The members of the α subfamily constitute AMPA-selective glutamate receptor channels, whereas the β and γ subfamilies include the subunits of the kainite-selective glutamate receptor channel. The ε and ζsubfamilies represent the subunits of the NMDA receptor channel. NMDA receptor channels with high activity are formed only when the distantly related ε and ζsubunits are expressed together. Four εsubunits of the NMDA receptor channel (the ε1,ε2,ε3, and ε4 subunits) are distinct with each other in distribution, function and regulation. In contrast to the wide distribution of theε1 and ζ1subunit mRNAs in various neural cells, the ε2 subunit mRNA is expressed selectively in the forebrain. Theε3 subunit mRNA is found predominantly in the cerebellum, whereas the ε4 subunit mRNA is weakly expressed in the brainstem and the diencephalon. Of the four ε/ζ heteromeric channels, theε4/ζ1 channel exhibits the highest apparent for L-glutamate and glycine, and the ε1/ζ1 channel the lowest affinities. Furthermore, the ε1/ζ1 channel is most sensitive to APV, whereas the ε3/ζ1 channel is most sensitive to 7-chlorokynurenate. The ε4/ζ1 channel is least sensitive to both antagonists. Remarkably, the ε3/ζ1and ε4/ζ1 channels are less sensitive to voltage-dependent Mg^<2+> block than the ε1/ζ1 and ε2/ζ1 channels. These findings suggest that the functional properties of the NMDA receptor channel are critically determined by the constituting ε subunit, and thus the molecular diversity of theε subunit family underlies the functional heterogeneity of the NMDA receptor channel.<br />Because the activity-dependent change in synaptic efficacy mediated by the NMDA receptor channel is found in forebrain regions such as the hippocampus and the visual cortex, it is likely that the ε1 and ε2 subunits highly expressed in the forebrain plays an important role in the synaptic plasticity. In accord with this assignment, theε1/ζ1 and ε2/ζ1 channels are highly sensitive to Mg^<2+> block, which is essential for the NMDA receptor channel to mediate the induction of the activity-dependent long-term potentiation of synaptic efficacy. On the other hand, the distribution of the ε3 subunit mRNA and the resistance of the ε3/ζ1 channel to Mg^<2+> block suggest that the ε3 subunit is a key component of cerebellar NMDA receptor channels mediating mossy fibre-granule cell synaptic transmission. We have also shown that treatment with TPA enhances the channel activity of the ε1/ζ1 and ε2/ζ1 channels, but not the ε3/ζ1and ε4/ζ1 c channels. Thus, modulation of the ε1/ζ1 and ε2/ζ1 channels by protein kinases may play a role in determining the threshold of the induction of long-term potentiation, since Ca^<2+> entry through the NMDA receptor channel triggers the persistent change in the efficacy of synaptic transmission. Voltage-dependent Mg^<2+> block is the key to the depolarization-dependent activation of the NMDA receptor channel, which is the basis of an activity-dependent change of synaptic efficacy. All subunits of the NMDA receptor channel possess asparagine in putative transmembrane segment M2 at the position corresponding to glutamine and arginine of the α subunits that determine the Ca^<2+> permeability of the AMPA-selective glutamate receptor channel. Replacement by glutamine of the asparagine strongly reduces the sensitivity to Mg^<2+> block of the ε2/ζ1 heteromeric NMDA receptor channel. Furthermore, the heteromeric channel with the mutation on both subunits becomes resistant to a channel blocker, MK-801. These findings suggest that the conserved asparagine in segment M2 constitutes a Mg^<2+> site of the NMDA receptor channel, and that the MK-801 site overlaps the Mg^<2+> site.
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