Research Interests

Remodeling

It is well documented that membrane excitability and excitation-contraction coupling are altered in the hypertrophied heart, and that ventricular hypertrophy is a risk factor for the development of life-threatening cardiac arrhythmias. Considerable evidence has accumulated to suggest that “electrical remodelling” occurs in the hypertrophied heart and that this reflects, at least in part, changes in the expression and/or the properties of the voltage-gated K⁺ (Kv) currents that underlie myocardial action potential repolarization. In ongoing studies, we are exploring the molecular mechanisms underlying Kv channel remodeling in a mouse model of pressure overload-induced left ventricular hypertrophy (LVH). These studies are focused on examining regional differences in the effects of LVH on the functional expression, the properties and/or the distributions of ventricular Kv channels, and on delineating the roles of elevated intracellular Ca²⁺, Kv channel accessory subunits and the actin cytoskeleton in regulating functional I_to,f channel expression. These studies will provide fundamentally important new insights into the effects of left ventricular hypertrophy on repolarizing Kvchannels, as well as into the molecular mechanisms underlying “electrical remodelling” in the hypertrophied heart.. In the long term, these insights should translate into more effective treatment strategies to reduce the risk of sudden death and the mortality and morbidity associated with myocardial hypertrophy and failure.

Neurons

Neurons in the central and peripheral nervous systems express a repertoire of voltage-gated K⁺ (Kv) channels that function to control resting membrane potentials, the waveforms of individual action potentials, repetitive firing patterns, and responses to synaptic inputs. In addition, these channels are important targets for the actions of a variety of transmitters, hormones and second messengers that regulate and modulate neuronal response properties. Ongoing studies are aimed at: determining the functional roles of Kv channels in controlling action potential waveforms and repetitive firing properties; defining the cellular and subcellular expression patterns of the Kv channel pore-forming (α) and accessory (Kvβ, minK/MiRPs, KChIPs, DPPXs) subunits that contribute to the formation of these channels; and, delineating the relationships between these subunits and functional neuronal Kv channels. Exploiting a combination of biochemical, molecular, electrophysiological and immunohistochemical approaches, ongoing studies are focused on determining the roles of the Kv channel accessory subunits, Kvβ1, KChIP3 and DPPX6, in determining the properties and the functional cell surface expression of IA channels in cortical projection neurons. In addition, experiments are underway to explore the role of Kv4 α subunit interactions with the actin cytoskeleton in controlling IA channel expression, properties and distribution. These studies are expected to provide important new insights into the roles of Kv channel accessory subunits and interactions with the actin cytoskeleton in the dynamic regulation of neuronal Kv channel macromolecular complexes.

Heart

Multiple types of voltage-gated K⁺ (Kv) channels are expressed in the mammalian heart. This diversity has a physiological significance in that the various Kv channels play distinct roles in controlling action potential waveforms and refractoriness. Although considerable progress has been made in identifying the Kv channel pore-forming (α) subunits that encode cardiac Kv channels, the functional roles of accessory subunits (minK/ MiRPs, Kvb, KChAP, KChIP, DPPX) are poorly understood. Studies in heterologous systems suggest that Kv accessory subunits can modulate the properties of a variety of Kv α subunit encoded channels and that each type of Kv channel likely is modulated by multiple accessory subunits. Other recent studies also suggest that cardiac Kv channels function as components of macromolecular protein complexes, comprising pore-forming and accessory subunits, as well as additional regulatory proteins that influence channel properties and mediate interactions with the actin cytoskeleton and the extracellular matrix. In vivo and in vitro approaches are being exploited in studies focused on delineating the physiological roles of the Kvβ1, KChIP2 and DPP6 subunits in the generation of the native Kv channels, I_to,f, I_to,s, I_K,slow and I_ss,, in intact cardiac (mouse ventricular) myocytes. The goals of these studies are to determine if cardiac Kv channels are regulated/modulated by multiple Kv accessory subunits and to test the hypothesis that Kv accessory subunits are multifunctional, regulating/modulating the functioning of multiple types of (Kv α subunit encoded) cardiac Kv channels. These studies should provide important new insights into the roles of Kv channel accessory subunits in the dynamic regulation of cardiac Kv channel macromolecular complexes.