Aspartate Residues of the Glu-Glu-Asp-Asp (EEDD) Pore Locus Control Selectivity and Permeation of the T-type Ca2+Channel α1G

Talavera, Karel; Staes, Mik; Janssens, Annelies; Klugbauer, Norbert; Droogmans, Guy; Hofmann, Franz; Nilius, Bernd

doi:10.1074/jbc.m103047200

Cited by 64 publications

(58 citation statements)

References 35 publications

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“…The effect of changing external pH has been studied with Ca v 3.1 (391) and Ca v 3.2 (95). In contrast to native channels, whose activity is affected by small deviations from pH 7.2, the recombinant channels are largely unaffected by pH changes in the 8.2 to 6.9 range.…”

Section: Electrophysiology Of Recombinant Channelsmentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,518

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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Section: Electrophysiology Of Recombinant Channelsmentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,518

1,446

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“…Three 1-subunits were cloned (1G, 1H and 1I or Cav3.1, Cav3.2 and Cav3.3), which were further extended by alternative splicing (36). This was a decisive step to allow the unraveling of structural determinants for permeation and kinetic T-type channel properties (41,44). Even more exciting, the functional role of T-type Ca 2+ channels could now be studied systematically, the distribution and expression pattern of the three T-type isoforms in several tissues could be unraveled, and, importantly, opened the possibility to use antisense and knock-out strategies to unveil the physiological and pathological role of these channel (for some reviews from the early period after cloning see 15,33,35,36,42,43).…”

Section: T-type Camentioning

confidence: 99%

Amazing T-type calcium channels: updating functional properties in health and disease

Nilius

Carbone

2014

Pflugers Arch - Eur J Physiol

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T-type Ca2+ channels have gained 15 years after cloning an immense interest as novel players in very unexpected cell functions and many relations to diseases have been discovered. This Special Issue provides a state of the art overview on novel functional properties of T-type Ca 2+ channels, unexpected cellular functions and most importantly will also summarizes and review the involvement of this "tiny, transient" type of Ca 2+ channels in several disease. It is tried to bridge the gap between molecular biophysical properties of T-type Ca 2+ channels and diseases providing finally a translational view on this amazing ion channel.

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“…All of the nonpolar amino acids were replaced by a polar amino acid, Ser, and the polar amino acids were replaced by a small, nonpolar 1 The abbreviations used are: GFP, green fluorescence protein; GST, glutathione S-transferase. amino acid, Ala. Gly is classified as a polar amino acid and was thus replaced by Ala. Because it has been reported that the negatively charged amino acids Glu and Asp in the transmembrane domain contribute to ion selectivity in voltage-gated Ca 2ϩ channels (30,31) and ECaC (32,33) and to interaction with channel blockers (34,35), the remarkable Asp 341 was replaced by each of 7 amino acids, Glu, Lys, Arg, Thr, Asn, Ala, and Leu, and the positively charged amino acid His 353 was also replaced by each of 3 amino acids, Asp, Arg, and Ala. The mutant genes bearing these single amino acid substitutions were then introduced into cells of the mid1-⌬5 mutant, and the resulting transformants were examined for viability and Ca 2ϩ accumulation after exposure to ␣-factor.…”

Section: H3 Is Essential For Mid1mentioning

confidence: 99%

Molecular Dissection of the Hydrophobic Segments H3 and H4 of the Yeast Ca2+ Channel Component Mid1

Tada¹,

Ohmori²,

Iida³

2003

Journal of Biological Chemistry

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The Saccharomyces cerevisiae MID1 gene product, Mid1, is composed of 548 amino acid residues, has four relatively hydrophobic segments named H1-H4, and functions as a Ca 2؉ -permeable, stretch-activated channel when expressed in mammalian cells. In some conditions Mid1 cooperates with Cch1, a yeast homolog of the ␣1 subunit of mammalian voltage-gated channels. To identify the important regions or amino acid residues necessary for Mid1 function, we employed in vitro sitedirected mutagenesis on H3 and H4 of Mid1 and expressed the resulting mutant genes in a mid1 null mutant to examine whether the mutant gene products are functional or not in vivo. Mutant Mid1 proteins lacking the whole H3 or H4 segment, H3De or H4De, did not complement the lethality and low Ca 2؉ accumulation activity of the mid1 mutant, although their localization and contents appeared to be normal, indicating that H3 and H4 are required for Mid1 function itself. Single amino acid exchange experiments on individual amino acid residues of H3 and H4 showed that 10 of 20 residues in H3 and 14 of 23 residues in H4 were important for the normal function of Mid1. In particular, we found four severe loss-of-function mutations, D341E, F356S, C373D, and C373R, and two interesting mutations leading to a high level of Ca 2؉ accumulation with a slightly low complementing activity, G342A and Y355A. The importance of these amino acid residues will be discussed.

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Aspartate Residues of the Glu-Glu-Asp-Asp (EEDD) Pore Locus Control Selectivity and Permeation of the T-type Ca2+Channel α1G

Cited by 64 publications

References 35 publications

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Amazing T-type calcium channels: updating functional properties in health and disease

Molecular Dissection of the Hydrophobic Segments H3 and H4 of the Yeast Ca2+ Channel Component Mid1

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