Molecular mechanisms involved in the activation and regulation of the α1-adrenergic receptor subtypes

doi:10.1016/S0014-827X(98)00021-4

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Volume 53, Issue 4, 30 April 1998, Pages 273-277

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Abstract

The adrenergic receptors (ARs) belong to the superfamily of membrane-bound G protein coupled receptors (GPCRs). Our investigation has focused on the structure–function relationship of the α_1b-AR subtype used as the model system for other GPCRs. Site-directed mutagenesis studies have elucidated the structural domains of the α_1b-AR involved in ligand binding, G protein coupling or desensitization. In addition, a combined approach using site-directed mutagenesis and molecular dynamics analysis of the α_1b-AR has provided information about the potential mechanisms underlying the activation process of the receptor, i.e. its transition from the `inactive' to the `active' conformation.

Section snippets

The α₁-adrenergic receptor subtypes

The receptors for a large number of hormones and neurotransmitters regulate cellular activity via the intermediary role of guanine nucleotide regulatory proteins (G proteins) [1]. Among these receptors, the adrenergic receptors (ARs) mediate the effects of epinephrine and norepinephrine by coupling to several of the major signalling pathways modulated by G protein. The adrenergic receptor family now includes nine different gene products, three β (β₁, β₂, β₃), three α₂ (α_2-C10, α_2-C4, α_2-C2) and

Structure–function relationship of the α₁-AR subtypes

The three cloned α₁-AR subtypes share similar structural features characterized by the seventh transmembrane domain (TMD) motif common to other G protein coupled receptors (Fig. 1). The TMDs of the three α₁-ARs show 65–75% of amino acid identity when compared among each other. Potential sites of phosphorylation by protein kinase C and A are present in the intracellular domains of all three receptor subtypes, suggesting that protein phosphorylation might play a role in receptor regulation.

The activation process of the α_1b-AR

The observation that mutations of GPCR can activate the receptor suggests that in the absence of agonist a structural constraint keeps the wild type receptor inactive (R), preventing sequences of the intracellular loops from interacting with the G proteins. Activating mutations might release such a constraint, triggering conversion into the active state (R*), which couples to G proteins. One hypothesis is that activating mutations mimic, at least to some extent, the conformational change

Acknowledgements

This work was supported by a grant from the Fonds National Suisse de la Recherche Scientifique (31-51043.97).

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α₁-Adrenoceptors seem to play key roles in cardiovascular, genitourinary, and central nervous system functions. This review will be focused on α_1D-adrenoceptors. These receptors have intrinsic activity, and many of the more commonly used antagonists are in reality inverse agonists. α_1D-Adrenoceptors are phosphorylated in the basal state, and the natural agonists, adrenaline and noradrenaline, increase their phosphorylation; similar effects are induced by direct activation of protein kinase C and through activation of nonadrenergic receptors. Interestingly, a large proportion of α_1D-adrenoceptors are located in intracellular vesicles. Such intracellular location can be changed to surface expression through the use of inverse agonists and coexpression of α_1B-adrenoceptors, which seem to act as pharmacological chaperons for proper plasma membrane insertion. The α_1D-adrenoceptor amino terminus seems to contain a signal that keeps the receptor intracellularly, but interaction with other proteins may also contribute. The precise relationship between the intrinsic activity, phosphorylation, and intracellular location is currently unknown. α_1D-Adrenoceptor activation induces contraction in a variety of vessels, and a role in the control of blood pressure has been suggested. Studies using young prehypertensive and adult spontaneously hypertensive rats as well as knockout mice suggest that vascular α_1D-adrenoceptors are involved in the genesis/maintenance of hypertension.
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Mice with altered α₁-adrenergic receptor (AR) genes have become important tools in elucidating the subtype-specific functions of the three α₁-AR subtypes because of the lack of sufficiently subtype-selective pharmacological agents. Mice with a deletion (knockout, KO) or an overexpression (transgenic, TG) of the α_1A-, α_1B-, or α_1D-AR subtypes have been generated. The α₁-ARs are the principal mediators of the hypertensive response to α₁-agonists in the cardiovascular system. Studies with these mice indicate that α_1A-AR and α_1B-AR subtypes play an important role in cardiac development and/or function as well as in blood pressure (BP) response to α₁-agonists via vasoconstriction. The α_1B- and α_1D-subtypes also appear to be involved in central nervous system (CNS) processes such as nociceptive responses, modulation of memory consolidation and working memory. The ability to study subtype-specific functions in different mouse strains by altering the same α₁-AR in different ways strengthens the conclusions drawn from these studies. Although these genetic approaches have limitations, they have significantly increased our understanding of the functions of α₁-AR subtypes.
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¹: Paper presented at the First Italian–Swiss Meeting on Medicinal Chemistry, Turin, Italy, September 1997.

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Molecular mechanisms involved in the activation and regulation of the α1-adrenergic receptor subtypes1

Abstract

Section snippets

The α1-adrenergic receptor subtypes

Structure–function relationship of the α1-AR subtypes

The activation process of the α1b-AR

Acknowledgements

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Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

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J. Biol. Chem.

Molecular mechanisms involved in the activation and regulation of the α₁-adrenergic receptor subtypes¹

The α₁-adrenergic receptor subtypes

Structure–function relationship of the α₁-AR subtypes

The activation process of the α_1b-AR