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首页> 外文学位 >Modulation of N-type calcium channels by G-protein betagamma subunits and regulators of G-protein signaling.
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Modulation of N-type calcium channels by G-protein betagamma subunits and regulators of G-protein signaling.

机译：由G蛋白betagamma亚基和G蛋白信号调节因子对N型钙通道的调节。

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摘要

Activation of G-protein coupled receptors (GPCRs) by neurotransmitters has been shown to induce inhibition of several types of voltage-dependent Ca2+ channels (VDCCs). At nerve terminals, this inhibition is important in modulating the strength of synaptic communication. N-type and P/Q-type Ca2+ channels are the major VDCCs located at the presynaptic nerve terminal and are involved in regulating neurotransmission, but only the N-type channels were studied here. The major mechanism underlying the GPCR inhibition of VDCCs is rapid, voltage-dependent, and mediated by direct binding of Gβγ subunits to the al subunit of Ca2+ channels. However, there are many examples of GPCR activation that do not produce VD inhibition of Ca2+ channels, although Gβγ subunits are always released upon receptor activation. In many cases these GPCRs are linked to Gq/11 family. The reasons for this specificity are not clear, but Gβ5γ2 has been shown to interact selectively with Gαq. The purpose of the present study was to understand the specificity of VDCC modulation by Gβγ released from Gq/11, family, using molecular, electrophysiological and cell imaging techniques.; Since there are multiple types of Gβ and Gγ subunits, many Gβγ combinations are possible. Initial studies were performed to test the ability of different Gβγ heterodimers to modulate N-type Ca2+ channels expressed in a stable cell line. The results indicated that all of the Gβ subunits could produce strong Ca 2+ inhibition. However, for Gβ5, the nature of the Gγ subunit involved was critical. Biochemical studies have shown that GGL-containing RGS proteins specifically interact with Gβ5. The ability of GGL-containing RGS proteins to modulate Ca2+ channel inhibition by Gβ5γ2 was studied. Electrophysiological studies demonstrated that these RGS proteins could antagonize Gβ5γ2-mediated N-type channel inhibition, and the effect required the GGL-domain. Association of GGL-containing RGS proteins with Gβ5 was confirmed in cells with fluorescence resonance energy transfer (FRET) studies. Finally, subcellular localization of Gβ5 and RGS11 proteins were studied using fluorescent and confocal microscopy. A model is proposed in which GGL-containing RGS proteins selectively modulate Gβ5γ2-mediated channel inhibition, and may partially underlie the specificity of VDCC modulation.
机译：研究表明，神经递质激活G蛋白偶联受体（GPCR）可以抑制几种类型的电压依赖性Ca 2 + 通道（VDCC）。在神经末梢，这种抑制作用对调节突触通讯的强度很重要。 N型和P / Q型Ca 2 + 通道是位于突触前神经末梢的主要VDCC，参与调节神经传递，但这里仅研究N型通道。 GPCR抑制VDCCs的主要机制是快速的，电压依赖性的，并通过Gβγ亚基与Ca 2+ 通道的al亚基直接结合来介导。然而，尽管Gβγ亚基总是在受体激活时释放，但是有许多GPCR激活的例子并没有对Ca 2 + 通道产生VD抑制作用。在许多情况下，这些GPCR与Gq / 11 家族相关。这种特异性的原因尚不清楚，但是已经表明Gβ5γ2与Gαq选择性地相互作用。本研究的目的是利用分子，电生理和细胞成像技术，了解由Gq / 11 家族释放的Gβγ调制VDCC的特异性。由于存在多种类型的Gβ和Gγ亚基，因此许多Gβγ组合都是可能的。进行了初步研究，以测试不同的Gβγ异二聚体调节稳定细胞系中表达的N型Ca 2 + 通道的能力。结果表明，所有的Gβ亚基均能产生强的Ca 2 + 抑制作用。然而，对于Gβ5，所涉及的Gγ亚基的性质至关重要。生化研究表明，含GGL的RGS蛋白与Gβ5特异性相互作用。研究了含GGL的RGS蛋白调节Gβ5γ2抑制Ca 2 + 通道的能力。电生理研究表明，这些RGS蛋白可以拮抗Gβ5γ2介导的N型通道抑制作用，并且这种作用需要GGL域。通过荧光共振能量转移（FRET）研究证实了含GGL的RGS蛋白与Gβ5的关联。最后，使用荧光和共聚焦显微镜研究了Gβ5和RGS11蛋白的亚细胞定位。提出了一种模型，其中含GGL的RGS蛋白选择性地调节Gβ5γ2介导的通道抑制，并且可能部分地基于VDCC调节的特异性。

著录项

  • 作者

    Zhou, Janice Y.;

  • 作者单位

    The University of Chicago.;

  • 授予单位 The University of Chicago.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 274 p.
  • 总页数 274
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;
  • 关键词

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