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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Lathrop, David A
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David et al. (2016) Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation. Cell 164:922-36
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
Isacoff, Ehud Y; Jan, Lily Y; Minor Jr, Daniel L (2013) Conduits of life's spark: a perspective on ion channel research since the birth of neuron. Neuron 80:658-74
Findeisen, Felix; Rumpf, Christine H; Minor Jr, Daniel L (2013) Apo states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain. J Mol Biol 425:3217-34
Findeisen, Felix; Tolia, Alexandra; Arant, Ryan et al. (2011) Calmodulin overexpression does not alter Cav1.2 function or oligomerization state. Channels (Austin) 5:320-4
Shaya, David; Kreir, Mohamed; Robbins, Rebecca A et al. (2011) Voltage-gated sodium channel (NaV) protein dissection creates a set of functional pore-only proteins. Proc Natl Acad Sci U S A 108:12313-8
Bagriantsev, Sviatoslav N; Minor Jr, Daniel L (2010) Small molecule ion channel match making: a natural fit for new ASIC ligands. Neuron 68:1-3
Findeisen, Felix; Minor Jr, Daniel L (2010) Structural basis for the differential effects of CaBP1 and calmodulin on Ca(V)1.2 calcium-dependent inactivation. Structure 18:1617-31
Minor Jr, Daniel L; Findeisen, Felix (2010) Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation. Channels (Austin) 4:459-74

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