Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, Organization for Life Science Advancement Programs, and Child Development Research Center, School of Medicine, University of Fukui, Eiheiji, Fukui, Japan.
Br J Pharmacol. 2012 Mar;165(5):1226-34. doi: 10.1111/j.1476-5381.2011.01591.x.
α(1)-Adrenoceptors are involved in numerous physiological functions, including micturition. However, the pharmacological profile of the α(1)-adrenoceptor subtypes remains controversial. Here, we review the literature regarding α(1)-adrenoceptors in the lower urinary tract from the standpoint of α(1L) phenotype pharmacology. Among three α(1)-adrenoceptor subtypes (α(1A), α(1B) and α(1D)), α(1a)-adrenoceptor mRNA is the most abundantly transcribed in the prostate, urethra and bladder neck of many species, including humans. In prostate homogenates or membrane preparations, α(1A)-adrenoceptors with high affinity for prazosin have been detected as radioligand binding sites. Functional α(1)-adrenoceptors in the prostate, urethra and bladder neck have low affinity for prazosin, suggesting the presence of an atypical α(1)-adrenoceptor phenotype (designated as α(1L)). The α(1L)-adrenoceptor occurs as a distinct binding entity from the α(1A)-adrenoceptor in intact segments of variety of tissues including prostate. Both the α(1L)- and α(1A)-adrenoceptors are specifically absent from Adra1A (α(1a)) gene-knockout mice. Transfection of α(1a)-adrenoceptor cDNA predominantly expresses α(1A)-phenotype in several cultured cell lines. However, in CHO cells, such transfection expresses α(1L)- and α(1A)-phenotypes. Under intact cell conditions, the α(1L)-phenotype is predominant when co-expressed with the receptor interacting protein, CRELD1α. In summary, recent pharmacological studies reveal that two distinct α(1)-adrenoceptor phenotypes (α(1A) and α(1L)) originate from a single Adra1A (α(1a)-adrenoceptor) gene, but adrenergic contractions in the lower urinary tract are predominantly mediated via the α(1L)-adrenoceptor. From the standpoint of phenotype pharmacology, it is likely that phenotype-based subtypes such as the α(1L)-adrenoceptor will become new targets for drug development and pharmacotherapy.
α(1)-肾上腺素受体参与许多生理功能，包括排尿。然而，α(1)-肾上腺素受体亚型的药理学特征仍然存在争议。在这里，我们从 α(1L)表型药理学的角度回顾了下尿路中的 α(1)-肾上腺素受体的文献。在三种 α(1)-肾上腺素受体亚型（α(1A)、α(1B)和 α(1D)）中，α(1a)-肾上腺素受体 mRNA 在包括人类在内的许多物种的前列腺、尿道和膀胱颈部转录最为丰富。在前列腺匀浆或膜制剂中，已检测到与哌唑嗪具有高亲和力的 α(1A)-肾上腺素受体作为放射性配体结合位点。前列腺、尿道和膀胱颈部的功能性 α(1)-肾上腺素受体对哌唑嗪的亲和力较低，表明存在非典型的 α(1)-肾上腺素受体表型（命名为 α(1L)）。在包括前列腺在内的各种组织的完整片段中，α(1L)-肾上腺素受体作为与 α(1A)-肾上腺素受体不同的结合实体存在。α(1L)-和 α(1A)-肾上腺素受体均特异性地不存在于 Adra1A（α(1a)）基因敲除小鼠中。α(1a)-肾上腺素受体 cDNA 的转染主要在几种培养细胞系中表达 α(1A)-表型。然而，在 CHO 细胞中，这种转染表达 α(1L)-和 α(1A)-表型。在完整细胞条件下，当与受体相互作用蛋白 CRELD1α 共表达时，α(1L)-表型占主导地位。总之，最近的药理学研究表明，两种不同的 α(1)-肾上腺素受体表型（α(1A)和 α(1L)）源自单个 Adra1A（α(1a)-肾上腺素受体）基因，但下尿路中的肾上腺素能收缩主要通过 α(1L)-肾上腺素受体介导。从表型药理学的角度来看，基于表型的亚型，如 α(1L)-肾上腺素受体，可能成为药物开发和治疗药理学的新靶点。
