Knock-out mice reveal tissue-specific roles of P2Y receptor subtypes in different epithelia
Knock-out mice reveal tissue-specific roles of P2Y receptor subtypes in different epithelia
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DOI：
10.1124/mol.63.4.773
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发表时间：
2003-04-01
影响因子：
3.6
通讯作者：
Dubyak, GR
中科院分区：
文献类型：
--
作者：
Dubyak, GR
ATP、UTP 及其相应的二磷酸盐在释放到细胞外区室或在细胞外区室内生成时充当细胞间信号分子。已在人类和其他脊椎动物基因组中鉴定出编码八种 G 蛋白偶联 P2Y 核苷酸受体亚型（von Kugelgen 和 Wetter，2000）、七种离子型 P2X 核苷酸受体亚型（North，2002）和至少九种不同的外切核苷酸酶（Zimmermann，2000）的基因。大多数哺乳动物细胞类型表达一种或多种核苷酸受体亚型以及用于降解和/或相互转化胞外核苷酸的核酸外切酶的各种组合。在本期《分子药理学》中，Robaye 等人 (2003) 描述了 P2Y4 受体缺失小鼠的产生和初始表型特征。他们的研究结果表明，P2Y4 受体是小肠空肠中盐和液体运输的主要 UTP 和 ATP 敏感调节剂。对上皮组织中基于核苷酸的信号传导的简要概述可能有助于充分理解这些发现的重要性。八种哺乳动物 P2Y 受体亚型中的大多数在广泛的组织和细胞类型中表达。然而，来自气道、肠道、肾脏和外分泌腺的上皮细胞和细胞已被证明特别重要，作为表达看似冗余的多种亚型（就 G 蛋白偶联和第二信使生成而言）P2Y 亚型的组织的例子，这些亚型分别用于调节不同的组织特异性功能。表 1 总结了 TIPS 最近综述的八种哺乳动物 P2Y 受体亚型的药理学特性（Abbracchio 等，2003）。根据其与特定 G 蛋白和效应蛋白的功能偶联，P2Y 受体可大致细分为五种 Gq 偶联亚型（P2Y1、P2Y2、P2Y4、P2Y6、P2Y11）和三种 Gi 偶联亚型（P2Y12、P213、P2Y14）。后一组包括最近克隆的 UDP-葡萄糖
ATP, UTP, and their corresponding disphosphates function as intercellular signaling molecules when released to, or generated within, extracellular compartments. Genes encoding eight G protein-coupled P2Y nucleotide receptor subtypes (von Kugelgen and Wetter, 2000), seven ionotropic P2X nucleotide receptor subtypes (North, 2002), and at least nine different ecto-nucleotidases (Zimmermann, 2000) have been identified in human and other vertebrate genomes. Most mammalian cell types express one or more subtypes of nucleotide receptor together with various combinations of the ecto-nucleotidases used for degrading and/or interconverting extracellular nucleotides. In this issue of Molecular Pharmacology, Robaye et al.(2003) describe the generation and initial phenotypic characterization of P2Y4 receptor null mice. Their findings demonstrate that the P2Y4 receptor is the dominant UTP-and ATP-sensitive regulator of salt and fluid transport in the jejunum of the small intestine. Full appreciation of the significance of these findings might be aided by a brief overview of nucleotide-based signaling in epithelial tissues.Most of the eight mammalian P2Y receptor subtypes are expressed in a broad range of tissues and cell types. However, epithelia and cells derived from the airways, gut, kidney, and exocrine glands have proven particularly significant as examples of tissues that express multiple subtypes of seemingly redundant—with regard to G protein coupling and second messenger generation—P2Y subtypes that are differentially used for the regulation of distinct tissue-specific functions. Table 1 summarizes the pharmacological properties of the eight mammalian P2Y receptor subtypes as recently reviewed in TIPS (Abbracchio et al., 2003). Based on their functional coupling to particular G proteins and effector proteins, P2Y receptors can be broadly subdivided into the five Gq-coupled subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) and three Gi-coupled subtypes (P2Y12, P213, P2Y14). The latter grouping includes the recently cloned UDP-glucose