Wai-Meng Kwok, PhD
Professor of Anesthesiology, Pharmacology & Toxicology
Medical College of Wisconsin
8701 Watertown Plank Road
Milwaukee, WI 53226-0509
Dr. Kwok received his B.A. in Physics from Kenyon College, Ohio, and his PhD in Biophysics from the University of Illinois at Urbana-Champaign. He completed his postdoctoral fellowship in cardiac electrophysiology and ion channel biophysics at the University of Rochester, NY.
The overall focus of Dr. Kwok’s laboratory is the investigation of ion channel modulation in the heart. There are two major areas of research currently underway. The first major area of investigation is on identifying a volatile anesthetic interaction site on a cardiac potassium channel, IKs, and characterizing the molecular determinants that modulate anesthetic action on this channel. The cardiac IKs is a major repolarizing current and its dysfunction results in the long QT syndrome, a clinical manifestation that can predispose an individual to fatal arrhythmias. In fact, a majority of the inherited form of LQTS (Type 1) is due to a dysfunction of IKs. Pharmacological inhibition of IKs can also potentially lead to long QT. IKs is very sensitive to inhibition by volatile anesthetics. Yet the molecular mechanism underlying the interaction between the anesthetic agent and IKs is unknown. We have previously reported that a phenylalanine, F340, located in the S6 domain of the channel’s pore-forming
a-subunit is critical to the inhibitory action of isoflurane on IKs. Furthermore, some of the identified inherited mutations of IKs linked to LQTS occur in the vicinity of F340. Thus, our goals are to further characterize the molecular interaction between IKs and volatile anesthetics, and to determine the impact of inherited IKs mutations on the channel’s pharmacology. To pursue these goals, the laboratory utilizes a combination of electrophysiological (patch clamp) and cellular/molecular (western blot analysis, immunohistochemistry, site-directed mutagenesis) techniques.
The second major area of research is the investigation of the mechanism underlying cardioprotection by anesthetic-induced preconditioning. We are particularly interested in the role of various ion channels involved in cardioprotection. Our previous work has characterized the interaction of volatile anesthetics with the sarcolemmal ATP-sensitive potassium (KATP) channel, one of the key components in the preconditioning pathway. In addition, we have reported on a persistent acceleration in the inactivation of the L-type calcium channel which can potentially lead to an attenuation of calcium overload. Recently, we have started to direct our focus to the modulation of ion channels of the mitochondria. A critical event in ischemia-reperfusion injury is the opening of the mitochondrial permeability transition pore (mPTP). Evidence suggests that the cardioprotective pathways converge onto the mitochondria and increase the threshold for mPTP opening, ultimately leading to cardioprotection. The mechanism underlying this modulation of mPTP is not known. Phosphorylation of key signal transduction mediators appears to be a necessary step. However, the identities of mitochondrial proteins that are phosphorylated have not been identified. Furthermore, opening of potassium channels on the inner mitochondrial membrane appears to be a key step toward cardioprotection. What triggers the opening and how these potassium channels are regulated are some of the important questions that are yet to be answered.
In the quest for understanding the role of mitochondrial ion channels in cardioprotection, we utilize two electrophysiological approaches. One is to incorporate purified mitochondrial proteins into planar lipid bilayers for biophysical characterizations. We have already successfully purified cardiac VDAC (voltage-dependent anion channel on the outer mitochondrial membrane) and ANT (adenine nucleotide translocator on the inner mitochondrial membrane), potential regulators of mPTP, and incorporated them into the lipid bilayer system. Experiments on the impact of phosphorylation on VDAC and ANT are currently underway. The other is to directly patch clamp the mitochondria and, specifically, the mitoplast (mitochondrion with a ruptured outer membrane). Patch clamp experiments are currently underway to characterize the ion channels found on the inner mitochondrial membrane.
To contact Dr. Kwok, please call 414-955-5683 or e-mail firstname.lastname@example.org.