Date of Award
Master of Science (MS)
For cardiovascular diseases such as high blood pressure, angina pectoris, and left ventricle hypertrophy; long-term activation of beta-adrenergic receptors is strongly linked to the progression of these diseases. A class of antagonistic drugs that target betaadrenergic receptors are collectively called beta-blockers. These drugs are commonly used to reduce the inotropic and chronotropic effects of beta-adrenergic receptor activation. This past decade has revealed that beta-blockers and other ligands are capable of functional selectivity at receptors. Functional selectivity describes the ability of ligands acting at 0 protein-coupled receptors (OPCRs) to preferentially activate or inhibit different signal transduction pathways. The studies on beta-adrenergic 2 receptors that explored functional selectivity showed that beta-blockers can be functionally selective by inhibiting the cAMP pathway while simultaneously activating ERK. The 0 protein coupled to beta-adrenergic receptors are the primary regulators of the cAMP, however there are a variety of pathways that can regulate ERK activity and few studies have tried to determine which pathway(s) the beta-blockers are targeting to cause this ERK activation. This is especially important for beta-adrenergic 2 receptors because they can activate ERK through multiple pathways (0 protein switching from G, to Oi/oprotein, beta-arrestin assisted or EOFR transactivation). ERK activation is linked to reversing cell damage caused by apoptosis signaling that results from G, activation by beta-adrenergic receptors. Understanding the specific pathways these beta-blockers can target for ERK activation would lead to better understanding of their therapeutic benefits. In this study we plan to elucidate the pathways several beta-blockers are targeting to activate ERK. In particular, we will investigate the role of clathrin-mediated receptor internalization and EGFR transactivation in beta-blocker-dependent ERK phosphorylation. In HEK 293 cells transfected with beta-adrenergic 2 receptors, we measured the changes in cAMP and ERK phosphorylation in response to the following beta-blockers labetalol, alprenolol, bucindolol, carvedilol, carazolol, leI 118,551 and propanolol. All of the beta-blockers studied inhibited isoproterenol-stimulated cAMP accumulation but stimulated the phosphorylation of ERK to varying degrees. Beta-blocker-mediated ERK phosphorylation was shown to be dependent on clathrin-dependent internalization and EGFR transactivation.
Ajumobi, Taiwo, "Beta-Blockers Act through Clathrin-Dependent Internalization and EGFR Transactivation to Promote ERK Phosphorylation" (2014). Graduate Thesis Collection. 267.