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17 results on '"Ratliff, Kevin S."'

2. Characterization of the SubstitutedN-Triazole Oxindole TROX-1, a Small-Molecule, State-Dependent Inhibitor of Cav2 Calcium Channels

Author

Swensen, Andrew M., primary, Herrington, James, additional, Bugianesi, Randal M., additional, Dai, Ge, additional, Haedo, Rodolfo J., additional, Ratliff, Kevin S., additional, Smith, McHardy M., additional, Warren, Vivien A., additional, Arneric, Stephen P., additional, Eduljee, Cyrus, additional, Parker, David, additional, Snutch, Terrance P., additional, Hoyt, Scott B., additional, London, Clare, additional, Duffy, Joseph L., additional, Kaczorowski, Gregory J., additional, and McManus, Owen B., additional

Published
2011
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3. Identification of Novel and Selective KV2 Channel Inhibitors

Author

Herrington, James, primary, Solly, Kelli, additional, Ratliff, Kevin S., additional, Li, Nina, additional, Zhou, Yun-Ping, additional, Howard, Andrew, additional, Kiss, Laszlo, additional, Garcia, Maria L., additional, McManus, Owen B., additional, Deng, Qiaolin, additional, Desai, Ranjit, additional, Xiong, Yusheng, additional, and Kaczorowski, Gregory J., additional

Published
2011
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14. Mitochondria unfold precursor proteins by unraveling them from their N-termini.

Author

Huang, Shihai, Ratliff, Kevin S., Schwartz, Michael P., Spenner, Jonathan M., and Matouschek, Andreas

Subjects
*MITOCHONDRIA, *DENATURATION of proteins, *ADENOSINE triphosphate
Abstract

Protein unfolding is a key step in the life cycle of many proteins, including certain proteins that are degraded by ATP-dependent proteases or translocated across membranes. The detailed mechanisms of these unfolding processes are not understood. Precursor proteins are unfolded and imported into mitochondria by a macromolecular machine that spans two membranes and contains at least nine different proteins. Here we examine import of a model precursor protein derived from the ribonuclease barnase and show that mitochondria unfold this protein by unraveling it from its N-terminus. Because barnase in free-solution unfolds by a different pathway, our results demonstrate that mitochondria catalyze unfolding in the way that enzymes catalyze reactions, namely by changing reaction pathways. The effectiveness of this mechanism depends on the structure of the N-terminal part of the precursor protein. [ABSTRACT FROM AUTHOR]

Published
1999

15. Characterization of the Substituted N-Triazole Oxindole TROX-1, a Small-Molecule, State-Dependent Inhibitor of Cav2 Calcium Channels

Author

Swensen, Andrew M., Herrington, James, Bugianesi, Randal M., Dai, Ge, Haedo, Rodolfo J., Ratliff, Kevin S., Smith, McHardy M., Warren, Vivien A., Arneric, Stephen P., Eduljee, Cyrus, Parker, David, Snutch, Terrance P., Hoyt, Scott B., London, Clare, Duffy, Joseph L., Kaczorowski, Gregory J., and McManus, Owen B.

Abstract

Biological, genetic, and clinical evidence provide validation for N-type calcium channels (CaV2.2) as therapeutic targets for chronic pain. A state-dependent CaV2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl CaV2.2 inhibitor used clinically. Supporting this notion, we recently reported that in preclinical models, the state-dependent CaV2 inhibitor (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1) has an improved therapeutic window compared with ziconotide. Here we characterize TROX-1 inhibition of Cav2.2 channels in more detail. When channels are biased toward open/inactivated states by depolarizing the membrane potential under voltage-clamp electrophysiology, TROX-1 inhibits CaV2.2 channels with an IC50of 0.11 μM. The voltage dependence of CaV2.2 inhibition was examined using automated electrophysiology. TROX-1 IC50values were 4.2, 0.90, and 0.36 μM at −110, −90, and −70 mV, respectively. TROX-1 displayed use-dependent inhibition of CaV2.2 with a 10-fold IC50separation between first (27 μM) and last (2.7 μM) pulses in a train. In a fluorescence-based calcium influx assay, TROX-1 inhibited CaV2.2 channels with an IC50of 9.5 μM under hyperpolarized conditions and 0.69 μM under depolarized conditions. Finally, TROX-1 potency was examined across the CaV2 subfamily. Depolarized IC50values were 0.29, 0.19, and 0.28 μM by manual electrophysiology using matched conditions and 1.8, 0.69, and 1.1 μM by calcium influx for CaV2.1, CaV2.2, and CaV2.3, respectively. Together, these in vitro data support the idea that a state-dependent, non–subtype-selective CaV2 channel inhibitor can achieve an improved therapeutic window over the relatively state-independent CaV2.2-selective inhibitor ziconotide in preclinical models of chronic pain.

Published
2012
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