The α1-adrenergic receptors: diversity of signaling networks and regulation

The α1-adrenergic receptor (AR) subtypes (α1a, α1b, and α1d) mediate several physiological effects of epinephrineand norepinephrine. Despite several studies in recombinant systems and insightfrom genetically modified mice, our understanding of the physiological relevance and specificity of the α1-AR subtypes is still limited. Constitutive activity and receptor oligomerization have emerged as potential features regulating receptor function. Another recent paradigm is that βarrestins and G protein-coupled receptors themselves can act as scaffolds binding a variety of proteins and this can result in growing complexity of the receptor-mediated cellular effects. The aim of this review is to summarize our current knowledge on some recently identified functional paradigms and signaling networks that might help to elucidate the functional diversity of the α1-AR subtypes in various organs

Study of the selectivity of alpha(1)-adrenergic antagonists by molecular modeling of alpha(1a)-, alpha(1b)-, and alpha(1d)-adrenergic receptor subtypes and docking simulations

Modeling of alpha(1a), alpha(1b), and alpha(1d) adrenergic receptor subtypes has been performed using InsightII software and bovine rhodopsin as a template. Adrenaline and noradrenaline, as endogenous agonists, were docked to validate the developed models, explore the putative binding sites, and calculate relative docking scores. alpha(1)-Adrenergic antagonists with the highest order of selectivity and activity at specific receptor subtypes were then chosen for docking into the corresponding receptor models. Docking simulations were performed using the FlexX module implemented in the Sybil program. PMF scoring functions of the obtained complexes calculated as relative to PMF scoring functions for noradrenaline-receptor subtype complexes were then used for correlation with selectivity on different alpha(1)-adrenergic subtypes. Good correlations were obtained for most receptor subtype-selectivity pairs: (1) using PMF scores calculated for ligands in complex with alpha(1a)-receptor subtype, r = 0.7503 for alpha(1a/1b) and r = 0.6336 for alpha(1a/1d) selectivity; (2) using PMF scores calculated for ligands in complex with alpha(1b) receptor subtype, r = 0.7632 for alpha(1a/1b) and r = 0.7061 for alpha(1b/1d) selectivity; (3) using PMF scores for ligands in complex with alpha(1d) receptor subtype, r = 0.7377 for alpha(1a/1d) and r = 0.9913 for alpha(1b/1d) selectivity.Peer reviewe