Date of Award


Degree Type


Degree Name

Master of Science (MS)



First Advisor

Pamela Crowell

Second Advisor

Medhane Cumbay

Third Advisor

Alexandre Erkine


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.