Elsevier

Archives of Medical Research

Volume 30, Issue 6, November–December 1999, Pages 449-458
Archives of Medical Research

Review
α1-Adrenoceptors: Subtypes, Signaling, and Roles in Health and Disease

https://doi.org/10.1016/S0188-0128(99)00059-7Get rights and content

Abstract

α1-Adrenoceptors mediate some of the main actions of the natural catecholamines, adrenaline, and noradrenaline. They participate in many essential physiological processes, such as sympathetic neurotransmission, modulation of hepatic metabolism, control of vascular tone, cardiac contraction, and the regulation of smooth muscle activity in the genitourinary system. It is now clear that α1-adrenoceptors mediate, in addition to immediate effects, longer term actions of catecholamines such as cell growth and proliferation. In fact, adrenoceptor genes can be considered as protooncogenes.

Over the past years, considerable progress has been achieved in the molecular characterization of different α1-adrenoceptor subtypes. Three main subtypes have been characterized pharmacologically and in molecular terms. Splice variants, truncated isoforms, and polymorphisms have also been detected. Similarly, it is now clear that these receptors are coupled to several classes of G proteins that, therefore, are capable of modulating different signaling pathways.

In the present article, some of these aspects are reviewed, together with the distribution of the subtypes in different tissues and some of the known roles of these receptors in health and disease.

Introduction

Adrenoceptors are a heterogeneous group of receptors that mediate the central and peripheral actions of the natural adrenergic amines, adrenaline, and noradrenaline. These receptors constitute a subfamily of the seven transmembrane domains/G protein-coupled receptors and have been divided into three major types based on their affinities for agonists and antagonists, the second messenger responses, and their aminoacid sequences, i.e., into α1-, α2-, and β-adrenoceptors (1). Three receptor isoforms have been cloned from each of these three major types, that is, nine receptors for adrenaline and noradrenaline have already been identified in molecular terms (1). The present review focuses exclusively on α1-adrenoceptors (α1-ARs).

Like other G protein-coupled receptors, α1-ARs are single-chain proteins that contain seven stretches of 20–28 hydrophobic aminoacids, probably representing transmembrane spanning domains 2, 3 (see Figure 1). Such hydrophobic domains are interconnected by hydrophilic loops, which according to current models are alternately exposed to the extra- and intracellular environment. The amino termini of these receptors are located extracellularly and contain consensus sites for N-linked glycosylation, while carboxyl termini are located intracellularly and contain consensus sites for phosphorylation by several protein kinases. The second and third intracellular loops are likely to be involved in the coupling of these receptors with heterotrimeric G proteins 1, 2, 3.

Section snippets

Receptor Subtypes

From the early 1980s, functional and radioligand-binding studies suggested that α1-ARs are heterogeneous (reviewed in References 3, 4). The powerful techniques of molecular biology allowed the cloning of cDNA and genes for three α1-ARs 5, 6, 7, 8. There was some confusion in correlating the pharmacologically defined receptors present in different tissues with the cloned receptors. This confusion has been resolved recently and a classification with the three major subtypes that follow is

Species Differences in Tissue Expression

α1-ARs are present in many tissues and play important roles in the maintenance of homeostasis. These receptors participate in many essential physiological functions, such as sympathetic neurotransmission, myocardial inotropy and chronotropy, modulation of hepatic metabolism, uterine contraction, regulation of water and electrolyte metabolism, modulation of vascular tone, and contraction of smooth muscle in the genitourinary system. Knowledge of α1-AR subtypes that participate in a given

Signal Transduction

It has been known for a long time that α1-ARs are coupled to phosphoinositide turnover/calcium signaling (29) (see Figure 2). However, it soon became clear that this signaling pathway did not completely explain all α1-adrenergic actions 30, 31 and that activation of α1-ARs stimulates multiple pathways 30, 31, 32, 33. Such multiple signaling seem to involve different G proteins and to depend on the repertoire of signaling devices expressed by the cells, i.e., to be cell-type-specific (33). A

Regulation of Receptor Function

Modulation of G protein-coupled receptor function (desensitization/resensitization) is a key event in the adaptation of cells to the changes in the internal milieu of an organism and to overall homeostasis. Different cellular processes, including receptor uncoupling from G proteins, internalization, recycling to the plasma membrane, degradation, and regulation of receptor gene expression (65), appear to be involved with different time frames. One initial event seems to be receptor

Smooth Muscle and Cardiac Hypertrophy

It has been observed that stress and hypertension, important risk factors for the development of atherosclerosis, are associated with elevated plasma catecholamine levels. As mentioned, catecholamines not only trigger immediate responses but also are able to induce long-term actions such as growth and proliferation. In vascular smooth muscle cells, catecholamines not only induce contraction but also influence proliferation. It has been observed that human and rat aorta smooth muscle cells

Vascular Smooth Muscle Contraction and Hypertension

Recent reports have shown that rat arteries express the three α1-ARs at the mRNA level (96). However, binding and functional studies usually indicate the predominance of one or two of the subtypes, and correlation between these different approaches is not always direct. This has greatly complicated the precise definition of the roles of each subtype in the two main functions of the vascular smooth muscle: contraction and the control of blood pressure.

Functional studies have shown that α1A-ARs

Benign Prostatic Hyperplasia

Benign prostatic hyperplasia is a very common illness in older men. Its symptoms are mainly associated with urinary outflow obstruction and can markedly impair quality of life. Surgical treatment, typically transurethral resection of the prostate, is highly effective but it is associated with significant morbidity. The prostatic gland expresses α1-ARs, and it has been argued that some cases of acute urine retention are caused by over-stimulation of these receptors. Pharmacological relaxation of

Acknowledgements

Research in our laboratories has been supported by grants from DGAPA (Mexico) (IN 200596) and CONACYT (Mexico) 27569-N (to JAG-S) and 28553-M (to RV-M).

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