Updates in the function and regulation of α1 -adrenoceptors

Abstract

α₁ -Adrenoceptors are seven transmembrane domain GPCRs involved in numerous physiological functions controlled by the endogenous catecholamines, noradrenaline and adrenaline, and targeted by drugs useful in therapeutics. Three separate genes, whose products are named α_1A -, α_1B -, and α_1D - adrenoceptors, encode these receptors. Although the existence of multiple α₁ -adrenoceptors has been acknowledged for almost 25 years, the specific functions regulated by each subtype are still largely unknown. Despite the limited comprehension, the identification of a single class of subtype-selective ligands for the α_1A - adrenoceptors, the so-called α-blockers for prostate dysfunction, has led to major improvement in therapeutics, demonstrating the need for continued efforts in the field. This review article surveys the tissue distribution of the three α₁ -adrenoceptor subtypes in the cardiovascular system, genitourinary system, and CNS, highlighting the functions already identified as mediated by the predominant activation of specific subtypes. In addition, this review covers the recent advances in the understanding of the molecular mechanisms involved in the regulation of each of the α₁ -adrenoceptor subtypes by phosphorylation and interaction with proteins involved in their desensitization and internalization. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

Figure 1

(a) Schematic representation of the classical Gq protein dependent signalling triggered by α₁‐adrenoceptor subtypes and (b) of the signalling triggered by receptor phosphorylation and interaction with β‐arrestin, which is also involved in receptor internalization. IP₃: inositol trisphosphate; PIP₂: phosphatidylinositol 4,5‐bisphosphate; PLC: phospholipase Cβ

Figure 2

Summary of the main functions identified for each of the α₁‐adrenoceptors subtypes in the cardiovascular system, genitourinary system, and CNS. Readers are referred to the text for the bibliography

Figure 3

Schematic representation of the substrates for phosphorylation currently identified in the three human α₁‐adrenoceptors (AR) subtypes (large red, yellow, and blue circles). Phosphorylated residues in the α_1A‐ and α_1D‐ adrenoceptors were identified by MS (Alcantara‐Hernandez et al., 2017; Alfonzo‐Méndez et al., 2018), whereas for the α_1B‐adrenoceptor, the residues were identified by site‐directed mutagenesis and functional analysis of the hamster orthologue (Diviani et al., 1997; in parenthesis are the sites defined for the hamster receptor). Below the diagram are the sequence alignments of the third intracellular loop and the carboxyl terminus (C‐tail) of the three human α₁‐adrenoceptor subtypes. Phosphorylated amino acids are marked in colour. Symbols: (a) “*” indicates single fully conserved residue; (b) “:” indicates conservative among subtypes; and (c) “.” non‐conservative among subtypes