Description of Research Expertise

RESEARCH INTERESTS
Central nervous system channelopathies; mechanisms of epilepsy and epileptogenesis; KCNQ voltage-gated potassium channels (structure, function, modulation, targeting, contribution to CNS excitability, openers as therapeutic drugs); axons: biophysical mechanisms, structure and evolution.

RESEARCH TECHNIQUES
Molecular biology, protein biochemistry, immunohistochemistry, electrophysiology, analytical chemistry (capillary HPLC, mass spectrometry, bioinformatics). Mammalian and non-mammalian (tunicates, lamprey, zebrafish) experimental systems.

RESEARCH SUMMARY
Voltage-gated ion channels are among the largest of mammalian gene families. Why has evolution conserved so many highly related channel genes? How can we tease out the functions played by particular channels in the nervous system? One approach is to seek clues from the phenotypes produced by naturally occurring mutations (Cooper and Jan, 1999, PNAS). Understanding how altering a channel's polypeptide sequence results in a specific neurological disease phenotype requires a multidisciplinary approach that both analyzes the channel's intrinsic biophysical properties and places them within native cellular, neuronal network, and developmental contexts. Recently we have been addressing these issues in studies of the KCNQ genes that are mutated in a hereditary form of human neonatal epilepsy. KCNQ genes encode voltage-gated potassium channels that underlie a highly regulated neuronal potassium current termed M-current. We have combined immunofluorescence and electron microscopy, molecular approaches, and electrophysiology to study the distribution of channels in mammalian circuits that are important for epilepsy and other neurological disorders. A key outcome is the observation (see Figure) that KCNQ2 and KCNQ3 are concentrated at the excitable portions of axons (i.e., the initial segments and nodes of Ranvier) by interaction with the adaptor protein, ankyrin-G. In these locations, we have proposed KCNQ2/3 channels have a unique role, as partners with voltage-gated sodium channels, in regulating the initiation and propagation of action potentials (Pan et al., 2006, J Neurosci). Electrophysiological studies of peripheral nodes of Ranvier support this hypothesis (Schwarz et al., 2006, J Physiol.). We are continuing to study the function of CNS KCNQ channels, and their potential as therapeutic targets. Mechanistic studies use patch clamp electrophysiology, computational modeling, proteomics, cell biology and molecular phylogenetics, in both mammalian and non-mammalian systems. Translational studies use human tissue and in vivo rodent models of symptomatic seizures, injury, and epileptogenesis. Inquiries from highly motivated students and scientifically and/or clinically trained post-doctoral scholars interested in ongoing projects are welcome.