Regulation of alpha-1B adrenergic receptor localization, trafficking, function, and stability

The alpha-1 adrenergic receptors (α₁ARs) play important roles in normal physiology and in many disease states, and understanding their signaling pathways and regulatory mechanisms is thus of considerable relevance, in particular for identifying pharmacological targets for therapeutic modulation. The expression, function, localization, trafficking, and stability of these receptors are all subject to complex regulation by diverse molecular mechanisms. This article highlights recent studies from our laboratory and others focused on the localization and trafficking of the alpha-1B adrenergic receptor (α_1BAR) subtype and on changes in its stability that are likely to be involved in regulating receptor expression. The role(s) of protein kinase C in α_1BAR sequestration, endocytosis, and extracellular signal-regulated kinase (ERK) activation are summarized, and evidence for α_1BAR localization in caveolae/rafts is presented. Receptor structural domains involved in the multiple steps and mechanisms of agonist-induced desensitization are described. Finally, aspects of α _1BAR structural stability that appear to control its drug-induced up- and down-regulation are discussed. Our understanding of regulation for the α_1BAR subtype provides a model for studies of the differential regulation of the other α₁AR subtypes and may lead to identification of new molecular targets for therapeutic intervention in a variety of disease states.