Browsing by Author "Snutch, Terrance P"

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    Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors
    (Elsevier Ltd., 2010-02-15) Pajouhesh, Hassan; Ding, Yanbing; Zhang, Lingyun; Pajouhesh, Hossein; Belardetti, Francesco; Simonson, Eric; Porreca, Frank; Mitscher, Lester A; Snutch, Terrance P; Feng, Zhong Ping; Morrison, Jerrie Lynn; Tringham, Elizabeth W.; Vanderah, Todd W.; Zamponi, Gerald W.
    A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC(50) values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.
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    T-type calcium channels functionally interact with spectrin (α/β) and ankyrin B
    (2018-05-02) Garcia-Caballero, Agustin; Zhang, Fang-Xiong; Hodgkinson, Victoria; Huang, Junting; Chen, Lina; Souza, Ivana A; Cain, Stuart; Kass, Jennifer; Alles, Sascha; Snutch, Terrance P; Zamponi, Gerald W
    Abstract This study describes the functional interaction between the Cav3.1 and Cav3.2 T-type calcium channels and cytoskeletal spectrin (α/β) and ankyrin B proteins. The interactions were identified utilizing a proteomic approach to identify proteins that interact with a conserved negatively charged cytosolic region present in the carboxy-terminus of T-type calcium channels. Deletion of this stretch of amino acids decreased binding of Cav3.1 and Cav3.2 calcium channels to spectrin (α/β) and ankyrin B and notably also reduced T-type whole cell current densities in expression systems. Furthermore, fluorescence recovery after photobleaching analysis of mutant channels lacking the proximal C-terminus region revealed reduced recovery of both Cav3.1 and Cav3.2 mutant channels in hippocampal neurons. Knockdown of spectrin α and ankyrin B decreased the density of endogenous Cav3.2 in hippocampal neurons. These findings reveal spectrin (α/β) / ankyrin B cytoskeletal and signaling proteins as key regulators of T-type calcium channels expressed in the nervous system.