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Functional Modulation of AMPA Receptors by R/G Editing and Auxiliary Subunits
Başlık:
Functional Modulation of AMPA Receptors by R/G Editing and Auxiliary Subunits
Yazar:
Wen, Wei, author.
ISBN:
9780438026827
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (180 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Li Niu Committee members: Haijun Chen; Jayanti Pande; Alexander Shekhtman; Jia Sheng; Mehmet Yigit.
Özet:
The propagation of information in the central nervous system is, in essence, the flow of ions. Neurons connect with each other to form neural circuits that perform distinct functions, and these connections are formed through synapses. Excitatory and inhibitory synapses determine the excitability of a neuron, which further dictates the firing of action potentials. The major ion channels that mediate the transmission at the excitatory synapses are ionotropic glutamate receptors, among which AMPA receptors are responsible for the fast excitatory transmission. Therefore, the functionalities of AMPA receptors substantially affect the information flow, and dysfunction of them could potentially cause many neurological disorders. AMPA receptors are tetrameric ion channels that are composed of four subunits GluA1 to GluA4; each subunit is further diversified by post-transcription (mRNA) and post-translation (protein) modifications. The expression of AMPA receptors variants across the central nervous system is tailored to the role played by synapses and neuron types in the neural circuits.
Two of the post-transcriptional modifications, the alternatively spliced flip/flop region and the R/G RNA editing site, are located in the ligand-binding domain with the R/G site directly preceding the flip/flop. However, it is unclear how R/G editing affects AMPA receptor channel gating, especially the channel opening process. Furthermore, how the R/G site and the adjacent flip/flop region interact with each other to modulate channel functions is also unknown. In Chapter 1 and 2, the modulatory role of the R/G site on channel gating kinetics was firstly investigated in GluA2 receptors, then in one of the major native AMPA receptor types, GluA1/2 receptors, using an ultrafast laser-pulse photolysis technique with halftime of 60 mus.
The results showed that R/G editing selectively modulated the channel gating kinetics of the flop variants of both GluA2 and GluA1/2 channels. Specifically, R/G-edited GluA2 channels closed faster, whereas R/G-edited GluA1/2 channels opened faster. Interestingly, for the GluA1/2 channel, the flip/flop region in GluA1, which did not exhibit any functional differences, became functionally significant in a GluA1/2 channel whose GluA2 was R/G-edited. Native AMPA receptors also co-exist with TARPs (Transmembrane AMPA receptor Regulatory Proteins), which strongly potentiates channel responses. However, the molecular mechanism underlying the potentiation is unclear. Explanations provided by previous studies include the increased EC50 values, reduced channel desensitization and/or deactivation, and increased channel conductance. However, there has been no report on the channel opening rate of AMPA receptors in the presence of TARPs. Responses of a receptor are tightly correlated to how fast its channel opens, therefore, investigating TARP-mediated effects on the channel opening kinetics of AMPA receptors will provide insights into the mechanisms underlying the observed potentiation. In Chapter 3, the channel opening kinetics of GluA1 and GluA2 channels was characterized, respectively, in the presence of the prototype TARP stargazin. Surprisingly, the results indicated that, rather than speeding up the channel opening rate, stargazin greatly reduced it. Furthermore, the EC50 values of both channels decreased significantly in the presence of stargazin, indicating that this reduction in the effective concentration was most likely the reason underlying the enhanced agonist-evoked amplitude. In contrast, an increase in the channel opening rate was unlikely to contribute to the potentiation.
In summary, the functions of AMPA receptors are subjected to fine-tuned regulations by both the modifications occurred in themselves and the auxiliary subunits. Findings from the first two chapters of this study indicate that GluA1/2 channels open substantially faster, possibly underlying some disease states where postsynaptic responses are abnormally enhanced. Results from the third chapter have contributed to the elucidation of a mechanism underlying TARP-mediated potentiation of AMPA receptors, which has advanced the understanding of the interactions between AMPA receptors and their auxiliary subunits. It also provides a reasonable explanation for AMPA receptors' high sensitivity to even a quantal of presynaptic glutamate release.
Notlar:
School code: 0668
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(681274.1) | 681274-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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