The HCN1 hyperpolarization-activated cyclic nucleotide regulated cation channel regulates the electrical activity of several types of neurons in the brain and spinal cord. Whereas forebrain-restricted HCN1 knockout mice show an improvement in hippocampal-dependent spatial learning and memory, the mice also have an enhanced susceptibility to seizures. In both humans and wild-type mice an initial precipitating seizure alters HCN1 expression, which is thought to contribute to development of epilepsy. One striking feature of HCN1 is that the channel plays distinct physiological roles in different neuron as a result of its differential targeting to distinct neuronal compartments. Whereas HCN1 is targeted to distal dendrites in hippocampal CA1 pyramidal neurons, the channel is targeted to presynaptic terminals in inhibitory basket cells. Moreover the pattern of channel expression is dynamic. Following a seizure, HCN1 becomes mislocalized in CA1 neurons, appearing in the soma instead of dendrites. How can a single macromolecule be differentially targeted to distinct locales based on neural identity? What signaling mechanisms might be important in regulating channel location? HCN1 channel expression and function are powerfully regulated by a brain-specific auxiliary subunit of HCN1 termed TRIP8b. The brain contains at least ten different TRIP8b splice variants that differ in their cellular localization and effects on channel surface expression. Knockdown of all TRIP8b isoforms greatly reduces expression and prevents targeting of HCN1 to CA1 distal dendrites. In contrast a TRIP8b hypomorph mouse that lacks all but two TRIP8b isoforms normally expressed in brain shows normal levels of HCN1 expression and dendritic targeting in CA1. What is the role of TRIP8b in targeting HCN1 to its distinct subcellular locales in different neurons? Do different TRIP8b isoforms differentially target HCN1 in different neurons? What signals define the identity of neural compartments, such as the distal dendrites? Might such signals regulate HCN1 trafficking through phosphorylation? Answers to such questions will provide insight into the mechanisms by which neurons regulate their electrical signaling properties and how such mechanisms might provide novel disease substrates.

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The electrical activity of nerve cells is controlled by specific ion channels, which are targeted to distinct regions of these cells. Changes in channel levels or localization can result in neurological disease, including epilepsy. This application is to identif the molecular mechanisms important for regulating the localization and expression of one particular channel critically important for brain function and disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Biophysics of Neural Systems Study Section (BPNS)
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Silberberg, Shai D
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Columbia University (N.Y.)
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New York
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Kupferman, Justine V; Basu, Jayeeta; Russo, Marco J et al. (2014) Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment. Cell 158:1335-47
Piskorowski, Rebecca; Santoro, Bina; Siegelbaum, Steven A (2011) TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron 70:495-509
Santoro, Bina; Hu, Lei; Liu, Haiying et al. (2011) TRIP8b regulates HCN1 channel trafficking and gating through two distinct C-terminal interaction sites. J Neurosci 31:4074-86
Santoro, Bina; Lee, Janet Y; Englot, Dario J et al. (2010) Increased seizure severity and seizure-related death in mice lacking HCN1 channels. Epilepsia 51:1624-7
Santoro, Bina; Piskorowski, Rebecca A; Pian, Phillip et al. (2009) TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron 62:802-13
Bell, Damian C; Turbendian, Harma K; Valley, Matthew T et al. (2009) Probing S4 and S5 segment proximity in mammalian hyperpolarization-activated HCN channels by disulfide bridging and Cd2+ coordination. Pflugers Arch 458:259-72
Dudman, Joshua T; Nolan, Matthew F (2009) Stochastically gating ion channels enable patterned spike firing through activity-dependent modulation of spike probability. PLoS Comput Biol 5:e1000290
Zhou, Lei; Siegelbaum, Steven A (2008) Pathway and endpoint free energy calculations for cyclic nucleotide binding to HCN channels. Biophys J 94:L90-2
Zhou, Lei; Siegelbaum, Steven A (2008) Effects of surface water on protein dynamics studied by a novel coarse-grained normal mode approach. Biophys J 94:3461-74
Zhou, Lei; Siegelbaum, Steven A (2007) Gating of HCN channels by cyclic nucleotides: residue contacts that underlie ligand binding, selectivity, and efficacy. Structure 15:655-70

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