Recent progress in α1-adrenergic receptor research
Review Article

Recent progress in α1-adrenergic receptor research

Zhong-jian Chen, Kenneth P Minneman1

Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, USA

1Correspondence to Dr Kenneth P MINNEMAN.
Phn 1-404-727-5985. Fax 1-404-727-0365.
E-mail kminneman@pharm.emory.edu

Abstract: α1-Adrenergic receptors (AR) play an important role in the regulation of physiological responses mediated by norepinephrine and epinephrine, particularly in the cardiovascular system. The three cloned α1-AR subtypes (α1A, α1B, and α1D) are G protein-coupled receptors that signal through the Gq/11 signaling pathway, each showing distinct pharmacological properties and tissue distributions. However, due to the lack of highly subtype-selective drugs, the functional roles of individual subtypes are still not clear. Development of new subtype-specific drugs will greatly facilitate the identification of the functions of each subtype. Conopeptide ρ-TIA has been found to be a new α1B-AR selective antagonist with different modes of inhibition at α1-AR subtypes. In addition, recent studies using genetically engineered mice have shed some light on α1-AR functions in vivo, especially in the cardiovascular system and brain. Several proteins have been shown to interact directly with particular α1-AR, and may be important in regulating receptor function. Receptor heterodimerization has been shown to be important for cell surface expression, signaling and internalization. These new observations are likely to help elucidate the functional roles of individual α1-AR subtypes.

Keywords: alpha1-adrenergic receptor; noncompetitive drug; protein-protein interaction; dimerization; cell surface expression

Submitted Apr 18, 2005. Accepted for publication Aug 28, 2005.

doi: 10.1111/j.1745-7254.2005.00224.x

Introduction

α1-Adrenergic receptors (AR) are members of the G protein-coupled receptor (GPCR) superfamily that mediate physiological responses to norepinephrine (NE) and epinephrine (EPI). Pharmacological analysis and molecular cloning have shown that this receptor family has three subtypes (α1A, α1B, α1D), which have different pharmacological properties and amino acid sequences[1]. Four C-terminal splice variants of the α1A-AR have been found[2,3]. Stimulation of all three subtypes results in activation of the Gq/11 signaling pathway, involving activation of phospholipase C, generation of the second messengers inositol (1,4,5) triphosphate and diacylglycerol, and mobilization of intracellular calcium. Because of their clinical importance, research on α1-AR has been very active for many years. Several recent reviews have summarized this research from different perspectives[4–9]. In this review, we mainly focus on recent developments in subtype-selective drugs, genetically engineered mouse models, interacting proteins, receptor dimerization, and factors controlling receptor cell surface expression.

α1-AR subtype selective drugs

Although all three α1-AR subtypes activate the same Gq/11 protein signaling pathway, their different tissue distributions suggest that they play distinct functional roles. For example, the α1A-AR subtype has been considered to be the dominant receptor subtype controlling benign prostatic hypertrophy, and is an important therapeutic target for treatment of this disease[10]. Therefore, identifying the specific functions of individual α1-AR subtypes is of considerable therapeutic interest. Unfortunately, this has proved difficult because of difficulties in identifying highly subtype-selective drugs. Despite extensive efforts to address this difficulty, only a few subtype-selective compounds have been characterized[11,12]. WB 4101[13], (+)-niguldipine[14], and 5-methylurapidil[15] have been used extensively as α1A-AR selective antagonists, and BMY7378[16] is widely used to characterize α1D-AR. However, there has been little progress in identifying α1B-AR selective antagonists. Chlorethyclonidine was originally characterized as an α1B-AR selective site-directed alkylating agent[17]; however, it has limited selectivity in alkylating the cloned subtypes, and is no longer widely used. Recently, a conopeptide isolated from a sea snail, known as ρ-TIA, was identified as a non-competitive α1B-AR antagonist[18,19] that may serve as an allosteric modulator, but acts as a competitive inhibitor at the other two subtypes[20,21]. This suggests that ρ-TIA may interact with a novel antagonist binding site specific to the α1B-AR and serve as a template for development of highly selective α1B-AR drugs.

Genetically engineered mouse models

Since attempts to elucidate the function of individual receptor subtypes has been limited by a lack of agonists, antagonists, and antibodies with adequate subtype selectivity, recent studies using genetically engineered mice have shed some light on the contributions of each subtype to physiological responses to NE and EPI. In general, α1-AR knockout mice do not show overt physical abnormalities (Table 1). Studies in knockout mice lacking a single α1-AR subtype have shown that all three subtypes seem to be involved in the regulation of blood pressure. Consistent with previous pharmacological characterization in vitro, studies in α1D-AR knockout mice have shown that the α1D-AR subtype plays a dominant role in aortic contraction[22]. Not only do genetically engineered mouse models help clear up some of the confusing cardiovascular effects mediated by individual subtypes, they also provide clues as to the functional roles of each subtype in the central nervous system, where these receptors are expressed in high concentrations, but their functions have been difficult to determine. The involvement of α1B-AR in the regulation of locomotion has been suggested by pharmacological manipulation[23]. Interestingly, knockout mice lacking α1B-AR also showed decreased locomotor hyperactivity in response to psychostimulants and opiates, suggesting that targeting the α1B-AR might be a useful therapeutic strategy in the treatment of drug abuse[24]. In addition to the altered phenotypes being examined in the knockout or transgenic models, the underlying molecular mechanisms have been investigated using olignucleotide microarrays. Alteration in the expression of NMDA receptors, GABAA receptors, and apoptotic and calcium regulatory genes shown in transgenic murine brains may provide a potential molecular basis for neurodegeneration induced by overexpressed constitutively active α1B-AR[25]. Despite the new insights provided by the genetically engineered studies, some discrepancies have been noticed from different studies, such as the contribution of α1B-AR in the aortic contractile response[26,27]. In addition, some of the altered phenotypes observed in the α1B-AR knockout model may result from compensatory effects of other receptor subtypes[28]. Further investigation using classic pharmacological approaches with highly subtype-selective drugs would be useful to facilitate future interpretations of those data.

Table 1
Table 1 Characteristics of α1-AR knockout or overexpression models.
Full table

Receptor interacting proteins

Recent studies have revealed that GPCR can interact with various cellular proteins in addition to the cognate G proteins, thereby expanding the receptor signaling network and establishing the distinct functional roles of closely-related receptor subtypes within the same family[29,30]. Those interacting proteins include cytoplasmic and membrane proteins that may play regulatory roles in receptor pharmacology, trafficking and signaling[31]. Although all three α1-AR subtypes couple to Gq/11 signaling pathways, previous studies have shown that the three subtypes can activate distinct downstream signaling components in the Gq/11 signaling pathway or couple to different signaling pathways[1]. Because of their relatively long C-termini, which have the least sequence homology among the three subtypes, most attention has been focused on finding binding partners interacting with this region. In addition, the sequence diversity in the third intracellular loop (I3 loop) is also attractive due to its importance in coupling to Gq/11. In a similar manner, it has been shown that the three β-AR subtypes differentially associate with a variety of proteins other than G proteins[32]. However, only a handful of interacting proteins have been identified for α1-AR subtypes (Table 2). A few of these interactions have been shown to have functional consequences, but most of them require further evaluation. For example, gC1qR and the mu2 subunit of the AP2 clathrin adaptor complex are involved in α1B-AR trafficking or internalization. Although transglutaminase II (Gh) is the first non-Gq/11 binding partner found to specifically associate with the α1B- and α1D-AR[33,34], the α1-AR signaling pathways seem to remain intact in Gh knockout mice[35]. Nevertheless, the search for novel binding partners should be considered as an alternative approach to study the molecular differences among the three α1-AR subtypes.

Table 2
Table 2 Receptor interacting proteins other than Gq/11 with potential functional roles.
Full table

Receptor dimerization

Unlike the conventional view that GPCR are monomers, a growing body of evidence indicates that GPCR are able to form dimers or oligomers that are required for their pharmacology, function and/or cell surface expression. This concept has gained great appreciation for the class III GPCR subfamily, including the GABAB receptors[36,37] and taste receptors[38]. However, the significance of class I GPCR dimerization has been under debate, due to difficulties in identifying unique functional responses or pharmacological properties. Our group has shown that the three α1-AR subtypes can form homodimers and subtype-specific heterodimers with other AR[39,40], which has been confirmed by data from other groups[41,42]. Because truncation of either the amino or the carboxyl terminus of the receptor does not affect receptor dimerization[40], the transmembrane domains or associated loops have been proposed to be involved in this interaction. Because the pharmacological analyses of the three cloned α1-AR subtypes in heterologous expression systems have not yet recapitulated all the receptor subtypes previously defined by pharmacological criteria in tissues, such as the α1L-AR[43], the newly found receptor dimers have been hypothesized to perform atypical α1-AR pharmacology, which has been seen in the opioid receptor family[44]. Although the homo- or heterodimers formed by α1A-AR C-terminal splice variants have failed to show any novel pharmacology when studied with existing selective drugs[45], it is still hard to conclude that the dimerization does not have effects on receptor pharmacology, because the available drugs are limited and the particular receptor dimers may yet be identified. On the other hand, the α1-AR subtype-specific dimerization has been found to be important for receptor trafficking and signaling (summarized in the next section).

α1D-AR cell surface expression

Theoretically, all three α1-AR subtypes should be present at the cell surface to be recognized by their highly hydrophilic natural ligands that are unlikely to cross cell membranes. However, when expressed in recombinant systems, the α1D-AR subtype has been noted to show almost exclusively intracellular expression[46,47], which makes them difficult to characterize. We recently reported that cell surface expression of the α1D-AR could be specifically rescued by coexpression with the α1B-AR but not the α1A-AR[48]. The coexpressed receptors seem to form a new receptor entity, and then modulate signaling and internalization of each receptor subtype in the complex. Recently, the β2-AR was also reported to be able to translocate α1D-AR[49]. Besides receptor dimerization, removal of the long amino-terminus of the α1D-AR has also been shown to facilitate translocation of intracellular receptors to the cell surface[50]. Subsequent studies using receptor N-terminal chimeras showed that this N-terminal domain might convey a retention signal to prevent receptor cell surface expression[51]. Moreover, the density of α1D-AR cell surface expression was shown to increase upon sequential truncation[52].

Future directions

In the past few years, our knowledge of the functional roles of the α1-AR family has been dramatically expanded using many different approaches. These findings generate several interesting directions that may be worth pursuing.

1 Further development of highly subtype-selective drugs, especially non-competitive antagonists: most of the specific α1-AR drugs available are competitive antagonists with moderate subtype-selectivity, which also target other cell surface proteins. Since the three α1-AR subtypes have relatively high homologies among the transmembrane domains that are believed to form the ligand binding pocket, designing new subtype-selective drugs that compete for this site has not been easy. However, development of noncompetitive drugs may be a good strategy because those drugs normally recognize a different site with less homology. This strategy has been successfully applied in designing highly subtype-selective drugs for other GPCR[53].

2 Investigate the physiological relevance of receptor oligomers: the success of this direction requires the advance of two other research fields, characterization of subtype-specific antibodies and development of new α1-AR drugs. Although receptor dimerization and protein–protein interactions have been identified in recombinant systems, and their importance in advancing our knowledge of the α1-AR family has been recognized, their physiological relevance in vivo cannot be confirmed and exploited without subtype-specific antibodies. On the other hand, new subtype-selective drugs may recognize the discrete pharmacology of receptor dimers, therefore expanding the existing cloned α1-AR family and providing new therapeutic targets.

3 Characterize subtype-specific interacting proteins: the growing list of GPCR interacting proteins has elucidated the molecular mechanisms of the differences among subtypes, which could lead to the development of drugs specifically targeting to such interactions. Because previous evidence suggests that the three α1-AR subtypes might couple to different signaling pathways, it is likely that more interacting proteins would be identified through the approaches that have been successfully used, such as yeast two-hybrid screenings and pull-down assays with fusion proteins.

4 Study the functional role of α1-AR in the central nervous system[5]. In fact, almost all typical and atypical antipsychotics are α1-AR antagonists, although they show little, if any, subtype selectivity[54]. In addition, tricyclic antidepressants are also α1-AR antagonists, and it is possible that this property may contribute to their therapeutic efficacy. We believe that studies focusing on those directions would further improve our understanding of the functional roles of each α1-AR subtype.

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Cite this article as: Chen Zj, Minneman KP. Recent progress in α1-adrenergic receptor research. Acta Pharmacologica Sinica 2005;26(11):1281-1287. doi: 10.1111/j.1745-7254.2005.00224.x