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J Biol Chem
2010 Jan 29;2855:3271-81. doi: 10.1074/jbc.M109.067660.
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Structural determinants of the high affinity extracellular zinc binding site on Cav3.2 T-type calcium channels.
Kang HW
,
Vitko I
,
Lee SS
,
Perez-Reyes E
,
Lee JH
.
???displayArticle.abstract??? Ca(v)3.2 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 Ca(v)3.2 and modulation by redox agents. His(191) is found on the extracellular face of the Ca(v)3.2 channel on the IS3-S4 linker and is not conserved in other Ca(v)3 channels. Mutation of the corresponding residue in Ca(v)3.1 to histidine, Gln(172), significantly enhances trace metal inhibition, but not to the level observed in wild-type Ca(v)3.2, 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.
Bourinet,
Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception.
2005, Pubmed
Bourinet,
Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception.
2005,
Pubmed
Chanda,
Gating charge displacement in voltage-gated ion channels involves limited transmembrane movement.
2005,
Pubmed
Chemin,
Specific contribution of human T-type calcium channel isotypes (alpha(1G), alpha(1H) and alpha(1I)) to neuronal excitability.
2002,
Pubmed
Chen,
Modulation of cloned skeletal muscle sodium channels by the scorpion toxins Lqh II, Lqh III, and Lqh alphaIT.
2000,
Pubmed
Choi,
Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels.
2007,
Pubmed
Ellinor,
Ca2+ channel selectivity at a single locus for high-affinity Ca2+ interactions.
1995,
Pubmed
,
Xenbase
Fox,
Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones.
1987,
Pubmed
Gomora,
Cloning and expression of the human T-type channel Ca(v)3.3: insights into prepulse facilitation.
2002,
Pubmed
Iftinca,
Regulation of neuronal T-type calcium channels.
2009,
Pubmed
Jacob,
The role of proline and glycine in determining the backbone flexibility of a channel-forming peptide.
1999,
Pubmed
Jeong,
Divalent metals differentially block cloned T-type calcium channels.
2003,
Pubmed
Kang,
A molecular determinant of nickel inhibition in Cav3.2 T-type calcium channels.
2006,
Pubmed
,
Xenbase
Kang,
Histidine residues in the IS3-IS4 loop are critical for nickel-sensitive inhibition of the Cav2.3 calcium channel.
2007,
Pubmed
,
Xenbase
Kozlov,
Distinct kinetics of cloned T-type Ca2 + channels lead to differential Ca2 + entry and frequency-dependence during mock action potentials.
1999,
Pubmed
Laussac,
13Carbon-nuclear magnetic resonance investigation of the Cu(II)-binding to the native sequence peptide representing the Cu(II)-transport site of human albumin. Evidence for the involvement of the beta-carboxyl side chain of aspartyl residue.
1980,
Pubmed
Lee,
Nickel block of three cloned T-type calcium channels: low concentrations selectively block alpha1H.
1999,
Pubmed
,
Xenbase
Li-Smerin,
Localization and molecular determinants of the Hanatoxin receptors on the voltage-sensing domains of a K(+) channel.
2000,
Pubmed
,
Xenbase
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Ma,
An extracellular Cu2+ binding site in the voltage sensor of BK and Shaker potassium channels.
2008,
Pubmed
,
Xenbase
Narahashi,
Characterization of two types of calcium channels in mouse neuroblastoma cells.
1987,
Pubmed
Nelson,
Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels.
2007,
Pubmed
Nelson,
Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate.
2007,
Pubmed
Obejero-Paz,
Y3+ block demonstrates an intracellular activation gate for the alpha1G T-type Ca2+ channel.
2004,
Pubmed
Perez-Reyes,
Molecular physiology of low-voltage-activated t-type calcium channels.
2003,
Pubmed
Planells-Cases,
Mutation of conserved negatively charged residues in the S2 and S3 transmembrane segments of a mammalian K+ channel selectively modulates channel gating.
1995,
Pubmed
,
Xenbase
Ramsey,
A voltage-gated proton-selective channel lacking the pore domain.
2006,
Pubmed
Rogers,
Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit.
1996,
Pubmed
Sato,
Molecular dissection of the contribution of negatively and positively charged residues in S2, S3, and S4 to the final membrane topology of the voltage sensor in the K+ channel, KAT1.
2003,
Pubmed
,
Xenbase
Shin,
T-type Ca2+ channels as therapeutic targets in the nervous system.
2008,
Pubmed
Silverman,
Mg(2+) modulates voltage-dependent activation in ether-à-go-go potassium channels by binding between transmembrane segments S2 and S3.
2000,
Pubmed
,
Xenbase
Silverman,
Structural basis of two-stage voltage-dependent activation in K+ channels.
2003,
Pubmed
,
Xenbase
Swartz,
Tarantula toxins interacting with voltage sensors in potassium channels.
2007,
Pubmed
Swenson,
K+ channels close more slowly in the presence of external K+ and Rb+.
1981,
Pubmed
Talavera,
Aspartate residues of the Glu-Glu-Asp-Asp (EEDD) pore locus control selectivity and permeation of the T-type Ca(2+) channel alpha(1G).
2001,
Pubmed
Tanabe,
Repeat I of the dihydropyridine receptor is critical in determining calcium channel activation kinetics.
1991,
Pubmed
Tiwari-Woodruff,
Electrostatic interactions between transmembrane segments mediate folding of Shaker K+ channel subunits.
1997,
Pubmed
,
Xenbase
Traboulsie,
Subunit-specific modulation of T-type calcium channels by zinc.
2007,
Pubmed
Tsien,
Calcium channels: mechanisms of selectivity, permeation, and block.
1987,
Pubmed
Vitko,
The I-II loop controls plasma membrane expression and gating of Ca(v)3.2 T-type Ca2+ channels: a paradigm for childhood absence epilepsy mutations.
2007,
Pubmed
Vitko,
Orientation of the calcium channel beta relative to the alpha(1)2.2 subunit is critical for its regulation of channel activity.
2008,
Pubmed
Zhang,
Contribution of hydrophobic and electrostatic interactions to the membrane integration of the Shaker K+ channel voltage sensor domain.
2007,
Pubmed
