Molecular studies of ion channel structure and function; synaptic transmission and plasticity in the mammalian brain.
We are studying the molecular mechanism by which external stimuli, such as chemical ligands and membrane voltage, activate different types of ion channels, integral membrane proteins that control electrical signaling in the nervous system. We study both cyclic nucleotide-gated channels, important for sensory signal transduction, and hyperpolarization-activated pacemaker channels, that control rhythmic spontaneous electrical activity in the brain and heart. Cloned channel genes are expressed in Xenopus oocytes and current flow through the channels is measured using the patch clamp technique. Mutations of cloned channel genes are then used to identify domains of the channel important for function.
In a separate set of experiments, we are analyzing synaptic transmission and plasticity in the mammalian hippocampus, a region of the brain important for learning and memory. Synapses between pairs of connected cells are recorded from hippocampal slices to investigate the mechanisms of long-term potentiation and long-term depression, two forms of activity-dependent synaptic plasticity. Two photon microscopy is used to image directly changes in presynaptic or postsynaptic function using fluorescent dyes. Using genetically engineered mice, the role of specific synaptic vesicle proteins in synaptic transmission and synaptic plasticity are also under study
- Liu, J. and Siegelbaum, S.A. (2000). Change of pore helix conformational state
upon opening of cyclic nucleotide-gated channels. Neuron 28, 899-909.
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Wainger, B.J., DeGennaro, M., Santoro, B., Siegelbaum, S.A. and Tibbs, G.R.
(2001). Molecular mechanism of cAMP-modulation of HCN pacemaker channels. Nature
411, 805-810.
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Zakharenko, S.S., Zablow, L. and Siegelbaum, S.A. (2001). Visualization of changes
in presynaptic function during long-term synaptic plasticity. Nature Neuroscience
4, 711-717.
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Zakharenko, S., Zablow, L. Siegelbaum, S.A. (2002). Altered presynaptic vesicle
release and cycling during mGluR dependent LTD. Neuron 35, 1099-1110.
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Wang, J., Chen, S., Nolan, M.F. and Siegelbaum, S.A. (2002). Activity-dependent
regulation of HCN pacemaker channels by cAMP: Signaling through dynamic allosteric
coupling. Neuron 36, 451-46
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