Thelong?termgoalsofthisprojectaretodevelopahigh?resolutionunderstandingofionchannelfunctionand regulation. Our studies focus on uncovering the architectural foundations that underlie the modulation of exemplarclassesfromthevoltage?gatedionchannel(VGIC)superfamilyandseektoaddressthefundamental question of how conformational changes in channel intracellular domains control and shape VGIC function. Many VGIC superfamily members, including Kv7 voltage?gated potassium channels and BacNaV bacterial voltage?gatedsodiumchannels,shareacommoncytoplasmicdomainarchitectureinwhichtheporedomain and a four?stranded coiled?coil frame a metastable membrane proximal domain that acts as a receiver for modulatory signals.
We aim to understand how such metastable domains sense inputs from the calcium sensor calmodulin in Kv7s and from temperature in BacNaVs and transmit signals to the channel pore. The prevalence of similar intracellular elements among diverse VGICs suggests that the principles derived from thesestudieswillhavebroadimpactindefininghowsuchintracellularmodulesshapechannelresponses.A secondeffortisdirectedatdefiningthearchitectureofaclassofintracellularendolysosomalVGICsknownas Two?Pore?Channels(TPCs)andthathavelimitedstructuralcharacterization.Thesechannelspossessaunique tandem transmembrane architecture and respond to a variety of intracellular signals, including calcium. Elaboration of the underlying structural framework of exemplar VGICs is essential for understanding how theseandotherVGICsareintegratedintointracellularsignalingpathwaysandfordevelopingnovelwaysto intervene to control channel function. Our efforts encompass a multidisciplinary approach that includes biochemical, biophysical, X?ray crystallographic, and cryo?electronmicroscopy studies to probe structure and electrophysiological measurements to dissect function. Because of their important role in human physiology, VGICs are the targets for drugs with great utility for the treatment of cardiac arrhythmias, hypertension, congestiveheartfailure,epilepsy,andchronicpain.Thus,understandingtheirstructuresandmechanismsof action at atomic level detail should greatly assist the development of valuable therapeutic agents for a wide rangeofhumanailments.

Public Health Relevance

Voltage-gated ion channels (VGICs) are the targets of drugs used to treat hypertension, arrhythmia, pain, epilepsy, and mood disorders. Our work aims to understand the molecular architecture that underlies VGIC function and modulation. Such understanding has direct relevance for development of more efficacious treatments of nervous system and cardiovascular disorders.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Freeman, Nancy
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Arrigoni, Cristina; Minor Jr, Daniel L (2018) Global versus local mechanisms of temperature sensing in ion channels. Pflugers Arch 470:733-744
Chang, Aram; Abderemane-Ali, Fayal; Hura, Greg L et al. (2018) A Calmodulin C-Lobe Ca2+-Dependent Switch Governs Kv7 Channel Function. Neuron 97:836-852.e6
Dang, Shangyu; Feng, Shengjie; Tien, Jason et al. (2017) Cryo-EM structures of the TMEM16A calcium-activated chloride channel. Nature 552:426-429
Minor Jr, Daniel L (2017) Channel surfing uncovers a dual-use transporter. EMBO J 36:3272-3273
Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David et al. (2016) Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation. Cell 164:922-36
Minor Jr, Daniel L (2016) Let It Go and Open Up, an Ensemble of Ion Channel Active States. Cell 164:597-8
Gaudet, Rachelle; Roux, Benoit; Minor Jr, Daniel L (2015) Insights into the molecular foundations of electrical excitation. J Mol Biol 427:1-2
Payandeh, Jian; Minor Jr, Daniel L (2015) Bacterial voltage-gated sodium channels (BacNa(V)s) from the soil, sea, and salt lakes enlighten molecular mechanisms of electrical signaling and pharmacology in the brain and heart. J Mol Biol 427:3-30
Shaya, David; Findeisen, Felix; Abderemane-Ali, Fayal et al. (2014) Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels. J Mol Biol 426:467-83
Xu, Qiang; Chang, Aram; Tolia, Alexandra et al. (2013) Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-helix complex provides insight into M current modulation. J Mol Biol 425:378-94

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