The roles played by highly truncated splice variants of G protein-coupled receptors.

Q2 Biochemistry, Genetics and Molecular Biology
Helen Wise
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引用次数: 55

Abstract

Alternative splicing of G protein-coupled receptor (GPCR) genes greatly increases the total number of receptor isoforms which may be expressed in a cell-dependent and time-dependent manner. This increased diversity of cell signaling options caused by the generation of splice variants is further enhanced by receptor dimerization. When alternative splicing generates highly truncated GPCRs with less than seven transmembrane (TM) domains, the predominant effect in vitro is that of a dominant-negative mutation associated with the retention of the wild-type receptor in the endoplasmic reticulum (ER). For constitutively active (agonist-independent) GPCRs, their attenuated expression on the cell surface, and consequent decreased basal activity due to the dominant-negative effect of truncated splice variants, has pathological consequences. Truncated splice variants may conversely offer protection from disease when expression of co-receptors for binding of infectious agents to cells is attenuated due to ER retention of the wild-type co-receptor. In this review, we will see that GPCRs retained in the ER can still be functionally active but also that highly truncated GPCRs may also be functionally active. Although rare, some truncated splice variants still bind ligand and activate cell signaling responses. More importantly, by forming heterodimers with full-length GPCRs, some truncated splice variants also provide opportunities to generate receptor complexes with unique pharmacological properties. So, instead of assuming that highly truncated GPCRs are associated with faulty transcription processes, it is time to reassess their potential benefit to the host organism.

Abstract Image

Abstract Image

G蛋白偶联受体的高度截断剪接变异体所起的作用。
G蛋白偶联受体(GPCR)基因的选择性剪接大大增加了可能以细胞依赖性和时间依赖性方式表达的受体同种异构体的总数。这种由剪接变异体的产生引起的细胞信号选择多样性的增加被受体二聚化进一步增强。当选择性剪接产生少于7个跨膜(TM)结构域的高度截断的gpcr时,在体外的主要影响是与内质网(ER)中野生型受体保留相关的显性阴性突变。对于组成活性(不依赖于激动剂)的gpcr,由于截断剪接变异体的显性负作用,它们在细胞表面的表达减弱,从而导致基础活性降低,这具有病理后果。当感染因子与细胞结合的共受体的表达由于内质网保留而减弱时,截短的剪接变异体可能反过来提供疾病保护。在这篇综述中,我们将看到保留在内质网中的gpcr仍然可以具有功能活性,但高度截断的gpcr也可能具有功能活性。尽管罕见,一些截断剪接变体仍然结合配体并激活细胞信号反应。更重要的是,通过与全长gpcr形成异源二聚体,一些截短的剪接变体也提供了产生具有独特药理特性的受体复合物的机会。因此,与其假设高度截断的gpcr与错误的转录过程有关,现在是时候重新评估它们对宿主生物的潜在益处了。
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来源期刊
Journal of Molecular Signaling
Journal of Molecular Signaling Biochemistry, Genetics and Molecular Biology-Biochemistry
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期刊介绍: Journal of Molecular Signaling is an open access, peer-reviewed online journal that encompasses all aspects of molecular signaling. Molecular signaling is an exponentially growing field that encompasses different molecular aspects of cell signaling underlying normal and pathological conditions. Specifically, the research area of the journal is on the normal or aberrant molecular mechanisms involving receptors, G-proteins, kinases, phosphatases, and transcription factors in regulating cell proliferation, differentiation, apoptosis, and oncogenesis in mammalian cells. This area also covers the genetic and epigenetic changes that modulate the signaling properties of cells and the resultant physiological conditions.
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