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Dive into the research topics where Ho-Won Kang is active.

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Featured researches published by Ho-Won Kang.


The Journal of Neuroscience | 2007

Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels

Michael T. Nelson; Jiwan Woo; Ho-Won Kang; Iuliia Vitko; Paula Q. Barrett; Edward Perez-Reyes; Jung-Ha Lee; Hee-Sup Shin; Slobodan M. Todorovic

Recent studies have demonstrated an important role for T-type Ca2+ channels (T-channels) in controlling the excitability of peripheral pain-sensing neurons (nociceptors). However, the molecular mechanisms underlying the functions of T-channels in nociceptors are poorly understood. Here, we demonstrate that reducing agents as well as endogenous metal chelators sensitize C-type dorsal root ganglion nociceptors by chelating Zn2+ ions off specific extracellular histidine residues on Cav3.2 T-channels, thus relieving tonic channel inhibition, enhancing Cav3.2 currents, and lowering the threshold for nociceptor excitability in vitro and in vivo. Collectively, these findings describe a novel mechanism of nociceptor sensitization and firmly establish reducing agents, as well as Zn2+, Zn2+-chelating amino acids, and Zn2+-chelating proteins as endogenous modulators of Cav3.2 and nociceptor excitability.


The Journal of Neuroscience | 2007

Molecular Mechanisms of Subtype-Specific Inhibition of Neuronal T-Type Calcium Channels by Ascorbate

Michael T. Nelson; Pavle M. Joksovic; Peihan Su; Ho-Won Kang; Amy Van Deusen; Joel P. Baumgart; Laurence S. David; Terrance P. Snutch; Paula Q. Barrett; Jung-Ha Lee; Charles F. Zorumski; Edward Perez-Reyes; Slobodan M. Todorovic

T-type Ca2+ channels (T-channels) are involved in the control of neuronal excitability and their gating can be modulated by a variety of redox agents. Ascorbate is an endogenous redox agent that can function as both an anti- and pro-oxidant. Here, we show that ascorbate selectively inhibits native Cav3.2 T-channels in peripheral and central neurons, as well as recombinant Cav3.2 channels heterologously expressed in human embryonic kidney 293 cells, by initiating the metal-catalyzed oxidation of a specific, metal-binding histidine residue in domain 1 of the channel. Our biophysical experiments indicate that ascorbate reduces the availability of Cav3.2 channels over a wide range of membrane potentials, and inhibits Cav3.2-dependent low-threshold-Ca2+ spikes as well as burst-firing in reticular thalamic neurons at physiologically relevant concentrations. This study represents the first mechanistic demonstration of ion channel modulation by ascorbate, and suggests that ascorbate may function as an endogenous modulator of neuronal excitability.


Journal of Biological Chemistry | 2006

A molecular determinant of nickel inhibition in Cav3.2 T-type calcium channels.

Ho-Won Kang; Jin-Yong Park; Seong-Woo Jeong; Jin-Ah Kim; Hyung-Jo Moon; Edward Perez-Reyes; Jung-Ha Lee

Molecular cloning studies have revealed that heterogeneity of T-type Ca2+ currents in native tissues arises from the three isoforms of Cav3 channels: Cav3.1, Cav3.2, and Cav3.3. From pharmacological analysis of the recombinant T-type channels, low concentrations (<50 μm) of nickel were found to selectively block the Cav3.2 over the other isoforms. To date, however, the structural element(s) responsible for the nickel block on the Cav3.2 T-type Ca2+ channel remain unknown. Thus, we constructed chimeric channels between the nickel-sensitive Cav3.2 and the nickel-insensitive Cav3.1 to localize the region interacting with nickel. Systematic assaying of serial chimeras suggests that the region preceding domain I S4 of Cav3.2 contributes to nickel block. Point mutations of potential nickel-interacting sites revealed that H191Q in the S3–S4 loop of domain I significantly attenuated the nickel block of Cav3.2, mimicking the nickel-insensitive blocking potency of Cav3.1. These findings indicate that His-191 in the S3–S4 loop is a critical residue conferring nickel block to Cav3.2 and reveal a novel role for the S3–S4 loop to control ion permeation through T-type Ca2+ channels.


The Journal of Physiology | 2006

Activation of protein kinase C augments T-type Ca2+ channel activity without changing channel surface density.

Jin-Yong Park; Ho-Won Kang; Hyung-Jo Moon; Sung-Un Huh; Seong-Woo Jeong; Nikolai M. Soldatov; Jung-Ha Lee

T‐type Ca2+ channels play essential roles in numerous cellular processes. Recently, we reported that phorbol‐12‐myristate‐13‐acetate (PMA) potently enhanced the current amplitude of Cav3.2 T‐type channels reconstituted in Xenopus oocytes. Here, we have compared PMA modulation of the activities of Cav3.1, Cav3.2 and Cav3.3 channels, and have investigated the underlying mechanism. PMA augmented the current amplitudes of the three T‐type channel isoforms, but the fold stimulations and time courses differed. The augmentation effects were not mimicked by 4α‐PMA, an inactive stereoisomer of PMA, but were abolished by preincubation with protein kinase C (PKC) inhibitors, indicating that PMA augmented T‐type channel currents via activation of oocyte PKC. The stimulation effect on Cav3.1 channel activity by PKC was mimicked by endothelin when endothelin receptor type A was coexpressed with Cav3.1 in the Xenopus oocyte system. Pharmacological studies combined with fluorescence imaging revealed that the surface density of Cav3.1 T‐type channels was not significantly changed by activation of PKC. The PKC effect on Cav3.1 was localized to the cytoplasmic II–III loop using chimeric channels with individual cytoplasmic loops of Cav3.1 replaced by those of Cav2.1.


Journal of Pharmacology and Experimental Therapeutics | 2006

Augmentation of Cav3.2 T-type calcium channel activity by cAMP-dependent protein kinase A.

Jin-Ah Kim; Jin-Yong Park; Ho-Won Kang; Sung-Un Huh; Seong-Woo Jeong; Jung-Ha Lee

Ca2+ influx through T-type Ca2+ channels is crucial for important physiological activities such as hormone secretion and neuronal excitability. However, it is not clear whether these channels are regulated by cAMP-dependent protein kinase A (PKA). In the present study, we examined whether PKA modulates Cav3.2 T-type channels reconstituted in Xenopus oocytes. Application of 10 μM forskolin, an adenylyl cyclase stimulant, increased Cav3.2 channel activity by 40 ± 4% over 30 min and negatively shifted the steady-state inactivation curve (V50 = -61.4 ± 0.2 versus -65.5 ± 0.1 mV). Forskolin did not affect other biophysical properties of Cav3.2 channels, including activation curve, current kinetics, and recovery from inactivation. Similar stimulation was achieved by applying 200 μM 8-bromo-cAMP, a membrane-permeable cAMP analog. The augmentation of Cav3.2 channel activity by forskolin was strongly inhibited by preincubation with 20 μM N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89), and reversed by subsequent application of 500 nM protein kinase A inhibitor peptide. The stimulation of Cav3.2 channel activity by PKA was mimicked by serotonin when 5HT7 receptor was coexpressed with Cav3.2 in Xenopus oocytes. Finally, using chimeric channels constructed by replacing individual cytoplasmic loops of Cav3.2 with those of the Nav1.4 channel, which is insensitive to PKA, we localized a region required for the PKA-mediated augmentation to the II-III loop of the Cav3.2.


Journal of Biological Chemistry | 2010

Structural determinants of the high affinity extracellular zinc binding site on Cav3.2 T-type calcium channels

Ho-Won Kang; Iuliia Vitko; Sang-Soo Lee; Edward Perez-Reyes; Jung-Ha Lee

Cav3.2 T-type channels contain a high affinity metal binding site for trace metals such as copper and zinc. This site is occupied at physiologically relevant concentrations of these metals, leading to decreased channel activity and pain transmission. A histidine at position 191 was recently identified as a critical determinant for both trace metal block of Cav3.2 and modulation by redox agents. His191 is found on the extracellular face of the Cav3.2 channel on the IS3-S4 linker and is not conserved in other Cav3 channels. Mutation of the corresponding residue in Cav3.1 to histidine, Gln172, significantly enhances trace metal inhibition, but not to the level observed in wild-type Cav3.2, implying that other residues also contribute to the metal binding site. The goal of the present study is to identify these other residues using a series of chimeric channels. The key findings of the study are that the metal binding site is composed of a Asp-Gly-His motif in IS3–S4 and a second aspartate residue in IS2. These results suggest that metal binding stabilizes the closed conformation of the voltage-sensor paddle in repeat I, and thereby inhibits channel opening. These studies provide insight into the structure of T-type channels, and identify an extracellular motif that could be targeted for drug development.


FEBS Letters | 2007

Histidine residues in the IS3–IS4 loop are critical for nickel‐sensitive inhibition of the Cav2.3 calcium channel

Ho-Won Kang; Hyung-Jo Moon; Seol-hee Joo; Jung-Ha Lee

We recently reported that a histidine (H191) in the S3–S4 loop of domain I is critical for nickel inhibition of the Cav3.2 T‐type Ca2+ channel. As in Cav3.2, two histidine residues are commonly found in the IS3–IS4 loops of mammalian Cav2.3 Ca2+ channels, which are also blocked by low micromolar concentrations of nickel. We show here by site‐directed mutagenesis and electrophysiology that both residues contribute to the nickel sensitivity of Cav2.3, with H183 being more critical than H179. These findings strongly suggest that both H179 and H183 in the IS3–IS4 loop are essential structural determinants required for nickel sensitive inhibition of the Cav2.3.


Journal of Biological Chemistry | 2004

Multiple Structural Elements Contribute to the Slow Kinetics of the Cav3.3 T-type Channel

Jin-Yong Park; Ho-Won Kang; Seong-Woo Jeong; Jung-Ha Lee

Molecular cloning and expression studies established the existence of three T-type Ca2+ channel (Cav3) α1 subunits: Cav3.1 (α1G), Cav3.2 (α1H), and Cav3.3 (α1I). Although all three channels are low voltage-activated, they display considerable differences in their kinetics, with Cav3.1 and Cav3.2 channels activating and inactivating much faster than Cav3.3 channels. The goal of the present study was to determine the structural elements that confer the distinctively slow kinetics of Cav3.3 channels. To address this question, a series of chimeric channels between Cav3.1 and Cav3.3 channels were constructed and expressed in Xenopus oocytes. Kinetic analysis showed that the slow activation and inactivation kinetics of the Cav3.3 channel were not completely abolished by substitution with any one portion of the Cav3.1 channel. Likewise, the Cav3.1 channel failed to acquire the slow kinetics by simply adopting one portion of the Cav3.3 channel. These findings suggest that multiple structural elements contribute to the slow kinetics of Cav3.3 channels.


PLOS Biology | 2010

A Post-Burst Afterdepolarization Is Mediated by Group I Metabotropic Glutamate Receptor-Dependent Upregulation of Cav2.3 R-Type Calcium Channels in CA1 Pyramidal Neurons

Jin-Yong Park; Stefan Remy; Juan Carlos Varela; Donald C. Cooper; Sungkwon Chung; Ho-Won Kang; Jung-Ha Lee; Nelson Spruston

The excitability of hippocampal pyramidal neurons is regulated by activation of metabotropic glutamate receptors, an effect that is mediated by modulation of R-type calcium channels.


Cell Calcium | 2009

Structural and biophysical determinants of single CaV3.1 and CaV3.2 T-type calcium channel inhibition by N2O

Peter Bartels; Kerstin Behnke; Guido Michels; Ferdi Groner; Toni Schneider; Margit Henry; Paula Q. Barrett; Ho-Won Kang; Jung-Ha Lee; Martin H.J. Wiesen; Jan Matthes; Stefan Herzig

We investigated the biophysical mechanism of inhibition of recombinant T-type calcium channels Ca(V)3.1 and Ca(V)3.2 by nitrous oxide (N(2)O). To identify functionally important channel structures, chimeras with reciprocal exchange of the N-terminal domains I and II and C-terminal domains III and IV were examined. In whole-cell recordings N(2)O significantly inhibited Ca(V)3.2, and - less pronounced - Ca(V)3.1. A Ca(V)3.2-prevalent inhibition of peak currents was also detected in cell-attached multi-channel patches. In cell-attached patches containing < or = 3 channels N(2)O reduced average peak current of Ca(V)3.2 by decreasing open probability and open time duration. Effects on Ca(V)3.1 were smaller and mediated by a reduced fraction of sweeps containing channel activity. Without drug, single Ca(V)3.1 channels were significantly less active than Ca(V)3.2. Chimeras revealed that domains III and IV control basal gating properties. Domains I and II, in particular a histidine residue within Ca(V)3.2 (H191), are responsible for the subtype-prevalent N(2)O inhibition. Our study demonstrates the biophysical (open times, open probability) and structural (domains I and II) basis of action of N(2)O on Ca(V)3.2. Such a fingerprint of single channels can help identifying the molecular nature of native channels. This is exemplified by a characterization of single channels expressed in human hMTC cells as functional homologues of recombinant Ca(V)3.1.

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