Propagation of electrical signals in the cardiac and nervous systems requires the concerted action of ion channel proteins and the molecules that modulate their activity. Despite decades of study by functional methods, a scarcity of high-resolution structural information limits our knowledge of how these molecules work. Understanding ion channels ultimately requires a high-resolution structural description of the channel proteins, their regulatory factors, and the conformational changes that accompany channel action. Our lab approaches this problem from the perspective of structural biology. Because channels are membrane proteins, a difficult class to investigate with any single structural technique, our efforts are directed at a multidisciplinary approach that involves both direct and indirect methods such as X ray crystallography and genetics for studying ion channel structure and function. Our current research aims to understand the central types of channels that are responsible for excitation (voltage-gated calcium channels) and inhibition (potassium channels) of electrical activity.

Calcium Channels

Voltage-gated calcium channels (Ca_Vs) are large, multisubunit, macromolecular machines that control calcium entry into cells in response to membrane potential changes. These molecular switches play pivotal roles in cardiac action potential propagation, neurotransmitter release, muscle contraction, calcium-dependent gene transcription, and synaptic transmission. Calcium influx is a potent activator of intracellular signaling pathways but is toxic in excess. As a result, its entry into cells is tightly regulated. Ca_Vs are major sources of activity-dependent calcium influx and possess a number of mechanisms that allow them to self regulate including: voltage dependent inactivation (VDI), calcium dependent facilitation (CDF), and calcium dependent inactivation (CDI). These processes arise from the concerted action different channel domains with the Ca_V β-subunits (Ca_Vβ) and the soluble calcium sensor calmodulin (CaM). While these Ca_V regulatory phenomena are well documented, understanding the molecular logic that underlies them remains elusive and awaits a molecular framework for proper interpretation. As a first step in revealing the molecular architecture that underpins Ca_V function, our research aims to determine the high resolution X ray crystal structures of Ca_V regulatory cytoplasmic domains alone and in complexes with Ca_Vβ and CaM. The structural data will then be used to inform functional experiments to clarify the mechanisms of channel action. Because of the central role of Ca_Vs in the cardiac and nervous systems, understanding how these channels function normally and misfunction in diseases will have important implications for human health.

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Potassium Channels

Potassium channels are the principal regulators of cellular electrical excitation. Our research efforts are focused on members of the voltage-gated (Kv and KCNQ) and inward rectifier (Kir) classes. We are particularly interested in understanding how cytoplasmic domains act to regulate channel function and serve as organizing platforms for components of cellular signaling cascades. Our potassium channel work uses a combination of X-ray crystallography, genetic selections, and electrophysiological experiments to explore how potassium channels function.

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[1] Structural understanding of ion channel action and regulation
[2] Molecular evolution of ion channel modulators for channels
[3] Structural understanding of membrane proteins that power the cell through their actions in mitochondria