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. These mechanisms depend critically on interactions of the pore-forming subunit with cytoplasmic proteins that regulate channel activity such as the calcium sensor proteins calmodulin and CaBP1. We are investigating the molecular basis of these phenomena. Due to the extraordinary challenges in studying mammalian membrane protein structure, our efforts are directed at understanding the function of the interactions between cytoplasmic components and the calcium sensor proteins. We are pursuing a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and electrophysiological measurements to dissect CaV function together with functional studies and molecular dynamics simulations to understand the structural basis of ion selectivity. 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.
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.
|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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