α1-Adrenoceptor subtypes

doi:10.1016/S0014-2999(99)00222-8

European Journal of Pharmacology

Volume 375, Issues 1–3, 30 June 1999, Pages 261-276

https://doi.org/10.1016/S0014-2999(99)00222-8 Get rights and content

Abstract

α₁-Adrenoceptors are one of three subfamilies of receptors (α₁, α₂, β) mediating responses to adrenaline and noradrenaline. Three α₁-adrenoceptor subtypes are known (α_1A, α_1B, α_1D) which are all members of the G protein coupled receptor family, and splice variants have been reported in the C-terminus of the α_1A. They are expressed in many tissues, particularly smooth muscle where they mediate contraction. Certain subtype-selective agonists and antagonists are now available, and α_1A-adrenoceptor selective antagonists are used to treat benign prostatic hypertrophy. All subtypes activate phospholipase C through the G_q/11 family of G proteins, release stored Ca²⁺, and activate protein kinase C, although with significant differences in coupling efficiency (α_1A>α_1B>α_1D). Other second messenger pathways are also activated by these receptors, including Ca²⁺ influx, arachidonic acid release, and phospholipase D. α₁-Adrenoceptors also activate mitogen-activated protein kinase pathways in many cells, and some of these responses are independent of Ca²⁺ and protein kinase C but involve small G proteins and tyrosine kinases. Direct interactions of α₁-adrenoceptors with proteins other than G proteins have not yet been reported, however there is a consensus binding motif for the immediate early gene Homer in the C-terminal tail of the α_1D subtype. Current research is focused on discovering new subtype-selective drugs, identifying non-traditional signaling pathways activated by these receptors, clarifying how multiple signals are integrated, and identifying proteins interacting directly with the receptors to influence their functions.

Introduction

Noradrenaline and adrenaline play important roles as neurotransmitters and hormones throughout the body. The adrenoceptors through which these compounds act are targets for many therapeutically important drugs. The adrenoceptors are subdivided into 3 families (α₁, α₂, β) based on their pharmacology, structure, and signaling mechanisms (Fig. 1; Bylund et al., 1994). Each family contains three or more subtypes, all of which are members of the G protein coupled receptor superfamily. These receptors consist of single polypeptide chains predicted to have 7 membrane spanning domains. The α₁-adrenoceptor family is of particular therapeutic interest because of its important role in control of blood pressure (Piascik et al., 1990; Bylund et al., 1994; Minneman and Esbenshade, 1994). These receptors are also abundant in brain, where their functional role is not yet clear, and play critical roles in controlling contraction and growth of smooth and cardiac muscle.

Section snippets

Existence of pharmacologically distinct α₁-adrenoceptor subtypes

The first strong evidence for pharmacologically distinct α₁-adrenoceptor subtypes came from studies of [ $^{3} H$ ]-prazosin binding to rat brain membranes (Morrow and Creese, 1986). Inhibition of [ $^{3} H$ ]-prazosin binding by WB 4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane) and phentolamine, but not by a variety of other antagonists, was characterized by a relatively shallow slope, indicating binding site heterogeneity. Morrow and Creese (1986)concluded that two distinct α₁-adrenoceptor

Cloning, structure, and splice variants

It is now clear that there are at least three α₁-adrenoceptor subtypes. Although only two subtypes (α_1A and α_1B) were easily distinguished pharmacologically, there was some evidence for additional heterogeneity (Minneman, 1988). Following the original cloning of the hamster α_1B-adrenoceptor by Cotecchia et al. (1988), two additional cDNAs have been cloned (Schwinn et al., 1990; Lomasney et al., 1991; Perez et al., 1991). For complicated reasons, the relationship between the pharmacologically

Expression and distribution

Radioligand binding assays have shown that α₁-adrenoceptors are expressed in a large number of tissues from a number of species. Unfortunately, specific antibodies to the three α₁-adrenoceptor subtypes are still not available, and the lack of highly subtype-selective antagonists makes quantitative analysis by radioligand binding methods difficult. Thus, mapping the distribution of these subtypes has been performed largely by analysis of mRNA expression patterns. Mapping studies have been

Selective agonists and antagonists

The affinities and selectivities of drugs for α₁-adrenoceptor subtypes have been determined primarily by competition for radioligand binding to heterologously expressed recombinant subtypes. Most antagonists, including the prototype α₁-adrenoceptor selective antagonist prazosin, show little or no selectivity between the three known α₁-adrenoceptor subtypes (Hancock, 1996), consistent with the structural homology of these subtypes in the transmembrane domains (Fig. 2). However, a variety of

Structural determinants of selectivity

The role of particular domains and/or amino acid residues of the receptors in determining their drug specificities have begun to be elucidated. The aspartate in the third transmembrane domain and the two serines in the fifth transmembrane domain that are conserved in all catecholamine receptors probably interact with the protonated amine and two hydroxyls of the catecholamines, in a manner analogous to that reported for the β₂-adrenoceptor. However, there is a significant difference in

G protein coupling

α₁-Adrenoceptors belong to the larger family of G_q/11-coupled G protein coupled receptors, which initiate signals by activating phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5, bisphosphate. This enzyme generates the second messengers inositol (1,4,5) trisphosphate, which releases Ca²⁺ from intracellular stores, and diacylglycerol, which synergizes with Ca²⁺ to activate protein kinase C (Minneman, 1988; Hieble et al., 1995; Fig. 3). The G_q/11 family of G proteins contains four

Coupling to other second messenger systems

A variety of other signaling pathways have also been shown to be activated by α₁-adrenoceptors (Minneman, 1988). These include Ca²⁺ influx, arachidonic acid release, and phospholipase D activation. Shortly after the existence of pharmacologically distinct α₁-adrenoceptor subtypes was recognized, Han et al. (1987b)suggested that the α_1A subtype coupled selectively to voltage-gated Ca²⁺ influx in smooth muscle. This hypothesis was supported by some studies (Tsujimoto et al., 1989; Han et al., 1990

Mitogenic responses

Mitogenic responses have traditionally been thought to be activated primarily by peptide growth factors, such as epidermal growth factor and nerve growth factor. Growth factor receptors consist of single polypeptide chains containing a single transmembrane domain. These receptors have intrinsic tyrosine kinase activity and dimerize in response to agonist occupation. Mitogenic responses are caused by a conserved cascade of events including receptor phosphorylation, binding of adaptor proteins,

Involvement of second messengers in mitogenic responses

Not surprisingly, activation of extracellular signal regulated protein kinases by receptors coupled to pertussis toxin-sensitive G_i proteins and pertussis toxin-insensitive G_q/11 proteins appear to involve different mechanisms (Hawes et al., 1995). Receptors coupled to G_i, such as α₂-adrenoceptors, appear to activate extracellular signal regulated protein kinases through release of βγ subunits, since responses to these receptors are often blocked by coexpression of an intracellular sequestrant

Activation of tyrosine kinases and small G proteins

Other than Ca²⁺ and protein kinase C, a number of studies have tried to identify other signaling molecules involved in activation of mitogen activated protein kinase pathways. It has been proposed that G_i coupled receptors activate mitogen activated protein kinase pathways through βγ activation of Ras. βγ dimers have been shown to be sufficient to induce Ras activation, as shown by the induced accumulation of Ras in the GTP-bound active form (Koch et al., 1994). Ras involvement in responses to G

Relative coupling efficiencies

It is clear that all three α₁-adrenoceptor subtypes couple to phospholipase C through the G_q/11 family to increase intracellular Ca²⁺. However, the three cloned subtypes have been found to have different efficiencies in activating this pathway. Schwinn et al. (1991)first reported that the α_1A-adrenoceptor was more efficient than the α_1B-adrenoceptor in activating inositol phosphate formation. Perez et al. (1993)studied the coupling of expressed α_1B- and α_1D-adrenoceptors to different signaling

Potential protein binding partners

Recently it has become clear that G protein coupled receptors can interact directly with proteins other than G proteins. It is becoming increasingly likely that these proteins form macromolecular signaling complexes similar to, but different from those formed by growth factor receptors. Discrete sequences on the C-terminal tails of a number of receptors have been shown to bind directly to proteins containing PDZ domains, and interaction with other types of proteins have also been reported. This

Future directions

Despite the enormous progress already made in identification and analysis of α₁-adrenoceptor subtypes, there are still many important questions to be answered. Development of more selective agonists and antagonists will allow a clearer understanding of the tissue distribution and functional roles of individual subtypes. It will be important to determine whether multiple subtypes coexist on single cells, and the impact this might have on signals generated by individual subtypes. The mechanisms

Acknowledgements

Supported by grants from the National Institutes of Health.

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Citation Excerpt :
Amongst the α1-adrenergic receptors (α1ARs), there are three subtypes, α1a, α1b and α1d (Bylund et al., 1994; Zhong and Minneman, 1999). While the subtypes of the receptor and some of their properties have been known for some time (Bylund et al., 1994; Zhong and Minneman, 1999; Chalothorn et al., 2002), their exact function and localization in various brain regions are still being elucidated. A major roadblock in understanding the functionality of each of the α1AR subtypes in the brain is the fact that subtype-specific pharmacological agents have yet to be developed (Giardina et al., 1996, 2003; Aono et al., 2015).
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Reviewα1-Adrenoceptor subtypes

Abstract

Introduction

Section snippets

Existence of pharmacologically distinct α1-adrenoceptor subtypes

Cloning, structure, and splice variants

Expression and distribution

Selective agonists and antagonists

Structural determinants of selectivity

G protein coupling

Coupling to other second messenger systems

Mitogenic responses

Involvement of second messengers in mitogenic responses

Activation of tyrosine kinases and small G proteins

Relative coupling efficiencies

Potential protein binding partners

Future directions

Acknowledgements

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Stimulation of alpha1A-adrenoceptors in Rat-1 cells inhibits extracellular signal-regulated kinase by activating p38 mitogen-activated protein kinase

Mol. Pharmacol.

Stimulation of phospholipase D via alpha1-adrenergic receptors in Madin-Darby canine kidney cells is independent of PKC-alpha and -epsilon activation

Mol. Pharmacol.

No role for Ca++ or protein kinase C in alpha-1A adrenergic receptor activation of mitogen-activated protein kinase pathways in transfected PC12 cells

Mol. Pharmacol.

Characterization of the alpha-1 adrenoceptor subtype mediating [3H]-arachidonic acid release and calcium mobilization in Madin-Darby canine kidney cells

J. Pharmacol. Exp. Ther.

Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy

Biochem. J.

International Union of Pharmacology nomenclature of adrenoceptors

Pharmacol. Rev.

Bombesin and neuromedin B stimulate the activation of p42(mapk) and p74(raf-1) via a protein kinase C-independent pathway in Rat-1 cells

Oncogene

Molecular cloning and expression of the cDNA for the hamster alpha-1-adrenergic receptor

Proc. Natl. Acad. Sci.

Regions of the alpha 1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function

Proc. Natl. Acad. Sci.

A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation

Nature

Comparison of alpha 1-adrenergic receptor subtypes and signal transduction in SK-N-MC and NB41A3 neuronal cell lines

Mol. Pharmacol.

Increased voltage-dependent calcium influx produced by alpha 1B-adrenergic receptor activation in rat medullary thyroid carcinoma 6-23 cells

Mol. Pharmacol.

Review
α₁-Adrenoceptor subtypes

Existence of pharmacologically distinct α₁-adrenoceptor subtypes

Characterization of the alpha-1 adrenoceptor subtype mediating [ $^{3} H$ ]-arachidonic acid release and calcium mobilization in Madin-Darby canine kidney cells