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: calcium dependent inactivation (CDI), calcium dependent facilitation (CDF), and voltage-dependent inactivation (VDI). 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 the interactions between cytoplasmic components and calcium sensor proteins that are important calcium-dependent regulation. 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.

Public Health Relevance

Calcium channels 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 calcium channel function. Such understanding has direct relevance for development of more efficacious treatments of nervous system and cardiovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080050-08
Application #
8239515
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2005-05-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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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
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
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Minor Jr, Daniel L (2017) Channel surfing uncovers a dual-use transporter. EMBO J 36:3272-3273
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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