The Cellular and Molecular Arrhythmia Research Laboratory at the University of Wisconsin is a multi-investigator laboratory involved in a wide range of research projects exploring the molecular function of ion channels in cardiac physiology, pharmacology and disease. The clinical application of this research is to cardiac arrhythmia, excitation-contraction coupling, myocardial preservation and myocardial regeneration. Five Cardiovascular Medicine (CVM) faculty members direct this laboratory:
The laboratory is composed of 16 -20 scientists including research scientists, graduate students, research technicians, post-doctoral fellows, CVM fellows and undergraduates. Multiple National Institutes of Health research grants and private sources fund the research programs. The Cellular and Molecular Arrhythmia Research Laboratory occupies 4500 ft2 in the Medical Sciences Center, and includes state-of-the-art molecular biology facilities, tissue culture, single cell electrophysiology equipment (patch clamp) and cellular fluorescence imaging equipment. Weekly conferences allow investigators at all levels to share their latest findings and discuss recent advances in the literature. In addition, multiple collaborative projects are underway with investigators in the Departments of Physiology, Pharmacology, Pharmacy, Anatomy and Surgery.
Current research projects include:
Acquired long QT syndrome molecular mechanisms: The acquired long QT syndrome can be induced in susceptible patients exposed to a broad array of different drugs. This has been a long-standing area of investigation by Craig January. Recent investigations by January and investigators in his lab have revealed that the likely target of these drugs is the promiscuous potassium channel, HERG. For example, cellular electrophysiology studies revealed many of the early antihistamine medications, including the astemizole metabolites, desmethylastemizole and norastemizole, are potent HERG blockers that can lead to prolongation of the action potential and associated risk of ventricular arrhythmias. Current work focuses on defining structure-activity relationships governing drug-blockade of HERG channels.
Antiarrhythmic drug molecular interactions: Longstanding investigations by Jonathan Makielski have led to an important understanding of the mechanism of interaction of antiarrhythmic drugs with voltage-dependent sodium channels in the heart. This interaction is the basis of action for many of the currently effective antiarrhythmic drugs. Using molecular biology techniques and heterologous expression of designer channels, Makielski's laboratory is defining a detailed model of blockage of the sodium channel by the antiarrhythmic drug lidocaine.
Regulation and function of ATP-dependent potassium channel (KATP): The KATP channel plays an important role in the electrical function of the heart, especially in pathological conditions such as ischemia, ischemic preconditioning and diabetes. Jonathan Makielski's laboratory initially demonstrated the critical regulation of the KATP channel by membrane phospholipids. Current research is focused on defining the molecular pathways involved in this regulation using mutagenesis techniques as well as knockout mice.
Neurohormonal regulation of L-type Ca2+ channels: As the initial trigger for excitation-contraction coupling in the heart, the L-type Ca2+ channel is exquisitely regulated by many signaling pathways. A variety of neurohormones in the heart, including endothelin-1 and angiotensin II, lead to the activation of protein kinase C. Timothy Kamp's laboratory, in collaboration with Jeffrey Walker, PhD (Physiology) has recently demonstrated that activating protein kinase C by these neurohormones or photorelease of diacylglycerol, a protein kinase C activator, up-regulates the activity of L-type Ca2+ channels. Current efforts are defining the mechanisms involved in this up-regulation using molecular biology, cellular electrophysiology and transgenic mice with conditional knockout of subunits of the channel complex.
Human embryonic stem cell derived cardiomyocytes characterization and applications: Embryonic stem (ES) cells are pluripotent cells capable of developing into specific cell types of all three germ layers including cardiomyocytes. Timothy Kamp's laboratory in collaboration with James Thomson (Dept. of Anatomy) has succeeded in differentiating human ES cells into cardiomyocytes. Initial electrophysiological characterization of these hES-derived cardiomyocytes have revealed distinct cell types including embryonic atrial, embryonic ventricular and nodal. Ongoing research is focused on optimizing the differentiation of human ES cells into cardiomyocytes and characterization of the resulting cardiomyocytes. Ultimately, these cells will have tremendous potential for cell-based therapies for a variety of heart diseases and will provide a useful cell culture model for a variety of basic research studies.
Craig T. January, MD, PhD, cellular electrophysiology, HERG potassium channels, long QT syndrome, Ca2+ channels
Timothy J. Kamp, MD, PhD, cellular electrophysiology, embryonic stem cells, excitation-contraction coupling, heart failure, Ca2+ channels, neurohormonal signaling, myocardial regeneration
Jonathan C. Makielski, MD, cellular electrophysiology, electrical remodeling, heart failure, Na channels, KATP channels
- Descriptions of the various labs and investigators that comprise the Cellular and Molecular Arrhythmia Research Program at UW-Madison
- Cellular and Molecular Arrhythmia Research Program information
- Tools, resources and links
- Cellular and Molecular Arrhythmia Research Program Publications
- Links to various scientific journals
- UW and Madison-area links