β1上腺体受体的合和激活 - 第三个细胞内循环的作用
Xingyu Qiu1,2, Kin Chao3, Siyuan Song1,2
1Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford, OX1 3QZ, U.K.
Journal of the American Chemical Society
|October 3, 2024
概括
通过微妙地改变核酸释放后的Gs结合,增强β1上腺素受体 (β1AR) 细胞内循环3 (ICL3) 的信号传递,从而促进cAMP的产生,而不是GDP的释放.
科学领域:
- 分子药理学
- 结构生物学
- 生物化学
背景情况:
- G蛋白结合受体 (GPCR) 是具有七个跨膜α螺旋体的关键膜蛋白.
- 细胞内循环3 (ICL3) 连接了5和6的跨膜螺旋,影响了受体的激活.
- 该β1上腺体受体 (β1AR) 是研究GPCR信号机制的关键目标.
研究的目的:
- 通过质谱学研究β1AR在G蛋白激活和信号传递中的作用.
- 阐明ICL3如何影响β1AR和Gs蛋白之间的相互作用.
主要方法:
- 原生质谱 (MS) 来评估受体-G蛋白合效率.
- 交换MS (HDX-MS) 用于监测受体激活时Gs的结构变化.
- 分子动力学 (MD) 模拟和功能性测试 (GDP释放,cAMP生产) 以验证发现.
主要成果:
- 完整的ICL3增强了β1AR与工程Gs子单元 (迷你Gs) 的优先合.
- HDX-MS 显示ICL3 诱导了一个明显的小Gs螺旋5 结合形态到β1AR.
- ICL3特别增强了cAMP的产生,这表明它在核酸释放后的信号放大中发挥了作用,而不会影响GDP的释放.
结论:
- 通过微调G蛋白激活,β1AR ICL3在GPCR信号传递中起着调节作用.
- 在核酸释放后,ICL3会影响Gs结合形状,影响下游的cAMP信号.
- 这些发现提供了GPCR信号调节的结构基础.
相关概念视频
Adrenergic Receptors: β Subtype
1.5K
β-adrenoceptors have varied sensitivities towards adrenaline, noradrenaline, and isoprenaline. The order of agonist potency is as follows:
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors...
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors...
1.5K
GPCRs Regulate Adenylyl Cylase Activity
5.3K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.3K
Adrenergic Receptors (Adrenoceptors): Classification
2.4K
Adrenergic receptors, or adrenoceptors, respond to the autonomic neurotransmitter noradrenaline and other endogenous catecholamine agonists. They are classified into two main families, α and β, based on their pharmacological response and are further subdivided depending on their location, elicited response, and affinity to specific agonists or antagonists.
α-Adrenoceptors
α-Adrenoceptors are classified into two main subtypes: α1 and α2. The α1 adrenoceptors,...
α-Adrenoceptors
α-Adrenoceptors are classified into two main subtypes: α1 and α2. The α1 adrenoceptors,...
2.4K
Activation and Inactivation of G Proteins
6.8K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
6.8K
Secondary Messengers in Hormone Action
2.1K
Water-soluble hormones cannot cross the plasma membrane, so they rely on protein receptors that span the membrane to trigger intracellular signaling pathways. These pathways then activate second messengers inside the cell, including cAMP or calcium ions.
Many hormones bind to transmembrane G protein-coupled receptors that connect to regulatory G proteins. These G proteins can then activate enzymes such as adenylyl cyclase or phospholipase C. Adenylyl cyclase converts ATP to cAMP, activating...
Many hormones bind to transmembrane G protein-coupled receptors that connect to regulatory G proteins. These G proteins can then activate enzymes such as adenylyl cyclase or phospholipase C. Adenylyl cyclase converts ATP to cAMP, activating...
2.1K
Amplifying Signals via Second Messengers
6.8K
Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...
6.8K


