The long-term goals of this project are to develop a high-resolution understanding of voltage-gated calcium channel (Cav) function and regulation. These molecular switches play pivotal roles in cardiac action potential propagation, neurotransmitter release, muscle contraction, calcium-dependent gene-transcription, and synaptic transmission. Calcium influx is a potent activator of intracellular signaling pathways but is toxic in excess. As a result, its entry into cells is tightly regulated. Cavs are major sources of activity-dependent calcium influx and possess a number of mechanisms that allow them to self-regulate including: voltage-dependent inactivation (VDI), calcium dependent facilitation (CDF), and calcium dependent inactivation (GDI). We are investigating the molecular basis of these phenomena. These phenomena depend critically on interactions of the pore-forming subunit with the cytoplasmic components that regulate channel activity. Due to the difficulties in studying mammalian membrane protein structure, our efforts are directed at understanding the function of two critical cytoplasmic components, the Cav P-subunit and calcium sensors, that are important for channel assembly and calcium-dependent regulation and that play major roles in orchestrating VDI, CDF, and GDI processes. We are pursuing a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and electrophysiological measurements to dissect Cav function. Because of their important role in human physiology, Cavs are the targets for drugs with great utility for the treatment of cardiac arrhythmias, hypertension, congestive heart failure, epilepsy, and chronic pain. Thus, understanding their structures and mechanisms of action at atomic level detail should greatly assist the development of valuable therapeutic agents for a wide range of human cardiac and neurological problems.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080050-05
Application #
7586053
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
2005-05-01
Project End
2010-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$359,123
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ely, Lauren K; Lolicato, Marco; David, Tovo et al. (2018) Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent. Structure 26:187-198.e4
Arrigoni, Cristina; Minor Jr, Daniel L (2018) Global versus local mechanisms of temperature sensing in ion channels. Pflugers Arch 470:733-744
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
Findeisen, Felix; Campiglio, Marta; Jo, Hyunil et al. (2017) Stapled Voltage-Gated Calcium Channel (CaV) ?-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function. ACS Chem Neurosci 8:1313-1326
Minor Jr, Daniel L (2016) Let It Go and Open Up, an Ensemble of Ion Channel Active States. Cell 164:597-8
Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David et al. (2016) Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation. Cell 164:922-36
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

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