The fundamental ability of a neuron to fire action potentials in response to synaptic input is largely determined by the electrical properties of its dendrites. One key ion channel that regulates the electrical properties of dendrites is the hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel. HCN channels operate at the threshold of excitability so small changes in the number, localization, voltage dependence, and cyclic nucleotide dependence of the channels can have a dramatic impact on the excitability of the cell. Our long term goal is to understand the molecular mechanisms for how HCN channels control neuronal excitability. Recently an auxiliary subunit of HCN channels in neurons was discovered, called TRIP8b. TRIP8b has a profound effect on the trafficking, voltage dependence, and cyclic nucleotide dependence of the HCN channels. In this grant, we propose to study the molecular mechanism for how TRIP8b binds to the HCN channel and regulates channel function. Our approach will be to combine x-ray crystallography, for atomic resolution structural information, with electrophysiology and fluorescence to study the functional channel in its native membrane environment. Our experiments will reveal the structure of the interaction between the HCN2 C-terminal region and TRIP8b at atomic resolution, the stoichiometry of the interaction, and the mechanism for TRIP8b regulation of the cyclic nucleotide-dependent and voltage- dependent gating of HCN2. These findings will provide a significant advance in our understanding of the structure and regulation of HCN channels as they exist in the neuron and further illuminate their role in the physiology and pathology of the brain.

Public Health Relevance

Ion channels are the transistors of the brain and thereby control everything from our senses to our thoughts. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are fundamentally involved in the electrical excitability of the neurons in our brain, and their dysfunction is responsible for some neurological diseases such as epilepsy. Our long term goal is to understand the molecular mechanisms for how HCN channels control neuronal excitability to enable us to develop targeted therapies for neurological diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Biophysics of Neural Systems Study Section (BPNS)
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Silberberg, Shai D
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University of Washington
Schools of Medicine
United States
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Bankston, John R; DeBerg, Hannah A; Stoll, Stefan et al. (2017) Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b. J Biol Chem 292:17794-17803
DeBerg, Hannah A; Bankston, John R; Rosenbaum, Joel C et al. (2015) Structural mechanism for the regulation of HCN ion channels by the accessory protein TRIP8b. Structure 23:734-44
Bankston, John R; Camp, Stacey S; DiMaio, Frank et al. (2012) Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels. Proc Natl Acad Sci U S A 109:7899-904