Photo of Brian Overholser
Tuesday, November 6, 2018

The Purdue College of Pharmacy is pleased to honor and recognize the outstanding research and scholarship generated by our faculty each month. This month we highlight Dr. Brian Overholser, Associate Professor of Pharmacy Practice.

Dr. Overholser’s recent publication, “Calcium/calmodulin-dependent protein kinase II regulation of IKs during sustained β-adrenergic receptor stimulation”, can be read in Heart Rhythm (June, 2018; DOI: 10.1016/j.hrthm.2018.01.024).

The research was conducted in the laboratories of Drs. Brian Overholser and Andy Hudmon. Also, in the proteomics core facility directed by Dr. Frank Witzmann with experiments performed by Dr. Xianyin Lai. The work was primarily performed by Tyler Shugg as part of his thesis work while at Purdue University. Additional trainees that contributed to this work were: Derrick E. Johnson, Minghai Shao and colleagues Theodore R. Cummins, PhDe; Michael Rubart-Von-der Lohe, MDf

Patients with heart failure are at an increased risk to develop arrhythmias which substantially contributes to their morbidity and mortality. The goal of this research was to assess the pathological regulation of a voltage-gate potassium channel (KCNQ1) during sustained beta-adrenergic receptor stimulation; a hallmark of heart failure. Using a phosphoproteomic approach coupled with biochemical and functional assessments, we identified specific sites of pathological regulation on KCNQ1 that result in functional alterations known to increase arrhythmia burden. We further demonstrated that these functional deficits in this potassium channel during sustained β-AR stimulation were mediated through enhanced CaMKII signaling; a known pathological response in heart failure. The reversal of CaMKII signaling alleviated the mechanistic and functional changes in the potassium channel to provide a guide for future studies on arrhythmia prevention during heart failure.

“This research has identified a novel molecular mechanism whereby heart failure may promote a susceptibility to arrhythmias,” said Dr. Overholser. “Our hope is that this work may ultimately be used as the foundation to inform a novel therapeutic strategy to decrease arrhythmia burden in these highly susceptible patients.”