Reviewα1-Adrenoceptor subtypes
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 []-prazosin binding to rat brain membranes (Morrow and Creese, 1986). Inhibition of []-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 (α1A and α1B) were easily distinguished pharmacologically, there was some evidence for additional heterogeneity (Minneman, 1988). Following the original cloning of the hamster α1B-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 Gq/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 Gq/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 α1A 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 Gi proteins and pertussis toxin-insensitive Gq/11 proteins appear to involve different mechanisms (Hawes et al., 1995). Receptors coupled to Gi, 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 Gi 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 Gq/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 α1A-adrenoceptor was more efficient than the α1B-adrenoceptor in activating inositol phosphate formation. Perez et al. (1993)studied the coupling of expressed α1B- and α1D-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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2018, NeuroscienceCitation 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).