investigator's application): Voltage-gated Ca2+ channels do a remarkable job of efficiently catalyzing the downhill flow of Ca2+ into cells, allowing Ca2+ permeation with rapid turnover rates, while also showing exquisite selectivity for Ca2+ over more abundant extracellular ions like Na+. A single opening of a Ca2+ channel may allow many thousands of Ca2+ ions to enter the cytoplasm generating a rise in [Ca2+]i that can control transmitter release, excitability, metabolism of gene expression. The structural determinants of Ca2+ channel selectivity and ion permeation are only partially understood. A set of four glutamate residues, located at a homologous position in each of the four repels of Ca2+ channel a1 subunits, lie within the pore and display high-affinity interactions with Ca2+ and other divalent cations. In this project, new experiments will be undertaken to gain more information about the nature of the Ca2+ channel pore and outer vestibule, and to clarify the mechanism by which the pore glutamates and other structures support ion permeation and block. The molecular determinants of the cut-off size of the pore's """"""""selectivity filter"""""""" and its permeability to internal ions will be studied. The outer vestibule of channel will be systematically probed using variants of conesnail peptide toxins as molecular calipers. Stations between bound toxin and permeating ions or channel inactivation will be examined in an effort to know more about external conformational changes during channel gating. Various configurations of the channel such as its protonated and Ca2+-blocked states will be incorporated into an increasingly sophisticated series of permeation models that will take account of the dimensions of the pore and the amino acid side chains within it. Kinetic features of permeation and block will also be modeled. Information about the structure of the pore will not only clarify the mechanism of permeation, but will also help explain the pore's ability to undergo high-affinity, Ca2+-dependent interactions with drugs such as 1,4-dihydropyridines.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Study Section
Physiology Study Section (PHY)
Program Officer
Baughman, Robert W
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Stanford University
Schools of Medicine
United States
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Cohen, Samuel M; Suutari, Benjamin; He, Xingzhi et al. (2018) Calmodulin shuttling mediates cytonuclear signaling to trigger experience-dependent transcription and memory. Nat Commun 9:2451
Mullins, Caitlin; Fishell, Gord; Tsien, Richard W (2016) Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops. Neuron 89:1131-1156
Cohen, Samuel M; Ma, Huan; Kuchibhotla, Kishore V et al. (2016) Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons. Neuron 90:292-307
Cohen, Samuel M; Li, Boxing; Tsien, Richard W et al. (2015) Evolutionary and functional perspectives on signaling from neuronal surface to nucleus. Biochem Biophys Res Commun 460:88-99
Rosenberg, Evan C; Tsien, Richard W; Whalley, Benjamin J et al. (2015) Cannabinoids and Epilepsy. Neurotherapeutics 12:747-68
Cohen, Samuel M; Tsien, Richard W; Goff, Donald C et al. (2015) The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia. Schizophr Res 167:98-107
Ma, Huan; Li, Boxing; Tsien, Richard W (2015) Distinct roles of multiple isoforms of CaMKII in signaling to the nucleus. Biochim Biophys Acta 1853:1953-7
Ma, Huan; Groth, Rachel D; Cohen, Samuel M et al. (2014) ?CaMKII shuttles Ca²?/CaM to the nucleus to trigger CREB phosphorylation and gene expression. Cell 159:281-94
Ma, Huan; Cohen, Samuel; Li, Boxing et al. (2013) Exploring the dominant role of Cav1 channels in signalling to the nucleus. Biosci Rep 33:97-101
Owen, Scott F; Tuncdemir, Sebnem N; Bader, Patrick L et al. (2013) Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Nature 500:458-62

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