STRUCTURE/FUNCTION OF ALPHA1 ADRENERGIC RECEPTORS

α1-肾上腺素能受体(ARs)在脑血管紧张素转换酶抑制中发挥重要作用 血压、鼻塞、肌肉生长等过程。 可以区分两个原生亚型(alpha1A和alpha1B 在药理上，已经克隆了三个亚型(Alpha1B，Alpha1C， 和字母1D)。尽管其中一个克隆的亚型(Alpha1D)是 最初被认为是对药理学定义的字母1A进行编码 亚类，最近的数据表明这是不太可能的。两国关系 必须了解克隆受体和天然亚型之间的关系， 以及获得的任何额外的cdna克隆，在生化和 可以清楚地理解alpha1-AR亚型的功能作用。 人SKNMC神经上皮瘤细胞表达至少两个α-ARs， 类似于字母1A和字母1B亚型。我们孤立了， 表达并部分鉴定了全长嵌合体 来自该细胞系的与大鼠同源的基因组/cDNA克隆 字母1D。我们将使用正义表达和反义敲除这一点 其他人在SKNMC细胞中的克隆以阐明 药理α1a亚型的已知克隆。如果他们是 不出所料，我们将通过以下方式获得全长的alpha1Acdna 表达克隆。有了这些克隆，我们将能够清楚地定义 药物的特异性、信号机制和相互作用 Alpha1-AR亚型。我们的主要目标包括： 1.明确已知的3个克隆与 药理学定义的α1亚型； 2.通过表达获得alpha1a亚型的全长cDNA 克隆； 3.确定不同的α1-AR受体亚型 优先耦合到不同的第二信使系统；以及 4.确定不同的亚型是否共存于同一单元格 有相加的、协同的或冗余的互动，这可能有助于 对于alpha1-AR亚型的数量和性质的混淆。 这些实验将阐明数字、信令机制和 α1-AR亚型的相互作用。因为作用于这些区域的药物 受体具有相当大的治疗重要性，这样的信息可能 有直接的临床影响。

alpha1-Adrenergic receptors (ARs) play important roles in control of blood pressure, nasal congestion, muscle growth, and other processes. Two native subtypes (alpha1A and alpha1B) can be distinguished pharmacologically, and three subtypes have been cloned (alpha1B, alpha1C, and alpha1D). Although one of the cloned subtypes (alpha1D) was originally thought to encode the pharmacologically defined alpha1A subtype, recent data suggests that this is unlikely. The relationship between the cloned receptors and the native subtypes must be understood, and any additional cDNA clones obtained, before the biochemical and functional roles of alpha1-AR subtypes can be clearly understood. Human SKNMC neuroepithelioma cells express at least two alpha1-ARs, resembling the alpha1A, and alpha1B subtypes. We have isolated, expressed, and partially characterized a full length chimeric genomic/cDNA clone from this cell line which is homologous to the rat alpha1D. We will use sense expression and antisense knockout of this and other human clones in SKNMC cells to clarify the relationship of the known clones to the pharmacological alpha1A subtype. If they are unrelated, as expected, we will obtain a full length alpha1A cDNA by expression cloning. With these clones we will be able to clearly define the drug specificities, signalling mechanisms, and interactions of alpha1-AR subtypes. Our major goals include: 1. To clearly define the relationship between the 3 known clones and the pharmacologically defined alpha1A subtype; 2. To obtain a full-length cDNA for the alpha1A subtype by expression cloning; 3. To determine whether different alpha1-AR receptor subtypes preferentially couple to different second messenger systems; and 4. To determine whether different subtypes co-existing in the same cell have additive, synergistic or redundant interactions which may contribute to the confusion about the number and properties of alpha1-AR subtypes. These experiments will clarify the number, signalling mechanisms, and interactions of alpha1-AR subtypes. Since drugs acting on these receptors have considerable therapeutic importance, such information may have direct clinical impact.