Agonist-Directed Desensitization of the β2-Adrenergic Receptor
نویسندگان
چکیده
The β(2)-adrenergic receptor (β(2)AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β(2)AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β(2)AR desensitization at the whole cell level.
منابع مشابه
Assembly of an A kinase-anchoring protein–β2-adrenergic receptor complex facilitates receptor phosphorylation and signaling
Phosphorylation of G-protein-coupled receptors by second-messenger-stimulated kinases is central to the process of receptor desensitization [1–3]. Phosphorylation of the β2-adrenergic receptor (β2-AR) by protein kinase A (PKA), in addition to uncoupling adenylate cyclase activation, is obligatory for receptormediated activation of mitogen-activated protein kinase (MAP kinase) cascades [4,5]. Al...
متن کاملCardiac physiologic regulation of sub-type specific adrenergic receptors in transgenic mice overexpressing β1- and β2-adrenergic receptors
OBJECTIVE Combination of β1-adrenergic receptor (AR) blockade and β2-AR activation might be a potential novel therapy for treating heart failure. However, use of β-AR agonists and/or antagonists in the clinical setting is controversial because of the lack of information on cardiac inotropic or chronotropic regulation by AR signaling. METHODS In this study, we performed hemodynamic evaluation ...
متن کاملCharacterising the Mechanism of Airway Smooth Muscle β2 Adrenoceptor Desensitization by Rhinovirus Infected Bronchial Epithelial Cells
Rhinovirus (RV) infections account for approximately two thirds of all virus-induced asthma exacerbations and often result in an impaired response to β2 agonist therapy. Using an in vitro model of RV infection, we investigated the mechanisms underlying RV-induced β2 adrenoceptor desensitization in primary human airway smooth muscle cells (ASMC). RV infection of primary human bronchial epithelia...
متن کاملDefective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma
β2-adrenergic receptor (β2AR) agonists (β2-agonist) are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation) by phosphorylation through G-protein coupled receptor kinases (GRKs) which mediate β-arrestin binding and βAR inte...
متن کاملSalmeterol Efficacy and Bias in the Activation and Kinase-Mediated Desensitization of β2-Adrenergic Receptors.
Salmeterol is a long-acting β2-adrenergic receptor (β2AR) agonist that is widely used as a bronchodilator for the treatment of persistent asthma and chronic obstructive pulmonary disease in conjunction with steroids. Previous studies demonstrated that salmeterol showed weak efficacy for activation of adenylyl cyclase; however, its efficacy in the complex desensitization of the β2AR remains poor...
متن کامل