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Associate Professor
Department of Neurosciences Case Western Reserve University
School of Medicine
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Associate Professor
Department of Neurosciences Case Western Reserve University
School of Medicine
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My main research interest is calcium signaling. Ionized free calcium (Ca2+) is important in regulating diverse cellular functions and serves as the critical link between a variety of physiological stimuli and their intracellular effectors. Specialized functions of Ca2+ in the nervous system include control of neurotransmitter release, membrane excitability and gene expression.
Since Ca2+ produces many of its intracellular effects by interacting with Ca2+ binding proteins according to bimolecular reaction kinetics, the ultimate effect of Ca2+ entry (e.g. through voltage-gated Ca2+ channels in the plasma membrane that open in response to membrane depolarization during an action potential or synaptic transmission) depends on the dynamics of the intracellular free Ca2+ concentration [Ca2+]. One of the main goals of my research is to understand the determinants of [Ca2+] dynamics and their modulation. This is interesting, and challenging, given the presence of intracellular compartments, such as mitochondria and the endoplasmic reticulum, that are endowed with specialized Ca2+ transport systems that permit them to either accumulate or release Ca2+ in a highly regulated manner.
Understanding Ca2+ signaling thus requires information about the changes in [Ca2+]i that occur within these compartments during stimulation and the specialized Ca2+ transport pathways (channels, pumps and exchangers) that are responsible for these changes. To obtain this information, a number of complementary experimental methods are employed, including the patch clamp technique to monitor Ca2+ movements across the plasma membrane under voltage-clamp, and variety of fluorescent Ca2+ indicators to monitor [Ca2+]i within different intracellular compartments and the spatial heterogeneity of [Ca2+]i within individual compartments as they occur during and after stimulation.
Another focus of our research is to understand how Ca2+ regulatory dysfunction contributes to disease. We are currently studying how mutations in voltage-sensitive Ca2+ channels (VSCCs) lead to neurodegeneration, using mouse cerebellar Purkinje neurons as a model system. Previous studies have shown that mutations in P/Q-type VSCCs lead to Purkinje cell loss, but the mechanism linking the Ca2+ channel defect to cell death is unknown. Mutations in the same channel subtype are responsible for several forms of inherited diseases in humans (e.g. familial hemiplegic migraine, episodic ataxia type-2, and spinocerebellar ataxia type 6) so the results of our studies are expected to contribute to an understanding of how Ca2+ regulatory dysfunction contributes to human genetic disease.
