Browsing by Author "Bladen, Chris"

Now showing 1 - 5 of 5
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    Block of T-type calcium channels by protoxins I and II
    (BioMed Central, 2014-05-09) Bladen, Chris; Hamid, Jawed; Souza, Ivana A.; Zamponi, Gerald W.
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    Common mechanisms of drug interactions with sodium and T-type calcium channels
    (The American Society for Pharmacology and Experimental Therapeutics, 2012-09) Bladen, Chris; Zamponi, Gerald W.
    Voltage-gated sodium (Na(v)) and calcium (Ca(v)) channels play important roles in physiological processes, including neuronal and cardiac pacemaker activity, vascular smooth muscle contraction, and nociception. They are thought to share a common ancestry, and, in particular, T-type calcium (T-type) channels share structural similarities with Na(v) channels, both with regard to membrane topology and with regard to gating kinetics, including rapid inactivation. We thus reasoned that certain drugs acting on Na(v) channels may also modulate the activities of T-type channels. Here we show that the specific Na(v)1.8 blocker 5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (A803467) tonically blocks T-type channels in the low micromolar range. Similarly to Na(v)1.8, this compound causes a significant hyperpolarizing shift in the voltage dependence of inactivation and seems to promote a slow inactivation-like phenotype. We further hypothesized that the structural similarity between T-type and Na(v) channels may extend to structurally similar drug-binding sites. Sequence alignment revealed several highly conserved regions between T-type and Na(v) channels that corresponded to drug-binding sites known to alter voltage-dependent gating kinetics. Mutation of amino acid residues in this regions within human Ca(v)3.2 T-type channels altered A803467 blocking affinity severalfold, suggesting that these sites may be exploited for the design of mixed T-type and Na(v) channel blockers that could potentially act synergistically to normalize aberrant neuronal activity.
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    Differential modulation of NMDA and AMPA receptors by cellular prion protein and copper ions
    (2018-10-25) Huang, Sun; Chen, Lina; Bladen, Chris; Stys, Peter K; Zamponi, Gerald W
    Abstract N-Methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are two major types of ionotropic glutamate receptors involved in synaptic transmission. However, excessive activity of these receptors can be cytotoxic and thus their function must be precisely controlled. We have previously reported that NMDA receptor activity is dysregulated following genetic knockout of cellular prion protein (PrPC), and that PrPC regulation of NMDA receptors is copper-dependent. Here, we employed electrophysiological methods to study NMDAR and AMPAR currents of cultured hippocampal neurons from PrPC overexpresser mice. We show that NMDA receptor current amplitude and kinetics are differentially modulated by overexpression of human or mouse PrPC. By contrast, AMPA receptor activity was unaffected. Nonetheless, AMPA receptor activity was modulated by copper ions in a manner similar to what we previously reported for NMDA receptors. Taken together, our findings reveal that AMPA and NMDA receptors are differentially regulated by PrPC, but share common modulation by copper ions.
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    Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants
    (Wiley-Liss, Inc., 2007-08-14) Heron, Sarah E.; Khosravani, Houman; Varela, Diego L.; Bladen, Chris; Williams, Tristiana C.; Newman, Michelle R.; Scheffer, Ingrid; Berkovic, Samuel F.; Mulley, John C.; Zamponi, Gerald W.
    The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures.
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    A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain
    (Elsevier, 2011-04-01) Hildebrand, Michael E.; Smith, Paula L.; Bladen, Chris; Eduljee, Cyrus; Xie, Jennifer Yanhua; Chen, Lina; Fee-Maki, Molly; Doering, Clinton J.; Mezeyova, Janette; Zhu, Yongbao; Belardetti, Francesco; Pajouhesh, Hassan; Parker, David B.; Arnerić, Stephen Peter; Parmar, Manjeet; Porreca, Frank; Tringham, Elizabeth W.; Zamponi, Gerald W.; Snutch, Terrance Preston
    Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.8 sodium channels and Ca(V)3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics.