Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart.

Schultz, D.; Mikala, Gábor; Yatani, Atsuko; Engle, Dorothy; Iles, David; Segers, Bart; Sinke, Richard J.; Weghuis, Daniël Olde; Klöckner, Udo; Wakamori, Minoru

doi:10.1073/pnas.90.13.6228

Cited by 118 publications

(71 citation statements)

References 23 publications

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“…The cardiac VDCC a1 subunit has been located on chromosome 12~12-pter (Powers et al, 1992;Schultz et al, 1993). The relevance that the genes encoding two distinct subunits of the VDCC are located on the same chromosome is unknown and may be fortuitous.…”

Section: Chromosomal Location Of Hp3mentioning

confidence: 99%

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Cloning, chromosomal location and functional expression of the human voltage‐dependent calcium‐channel β3 subunit

Collin

Lory

Taviaux

et al. 1994

European Journal of Biochemistry

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Service de gyntcologie-obstetrique, HBpital Carremeau, Nimes, France A novel human-voltage-dependent-calcium-channel (VDCC) P subunit was isolated from a 9-week-old human total-embryo cDNA library. Of the four genes encoding P-subunit isoforms that have been identified in-animal species, this isoform shares strong similarity with the rat and rabbit &-related gene product and is referred to here as HP3 subunit. The HP3 isoform is the second P subunit identified in human. Its open reading frame encodes a 482-amino-acid protein with a predicted molecular mass of 54.571 kDa. The Hp3 mRNA is expressed mostly in brain, smooth muscle and ovary. The gene for the human Hp, was specifically localized on chromosome 12q13. The cloned HP, subunit was further expressed in Xenopus oocytes to demonstrate its ability to modulate VDCC activity.

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Section: Chromosomal Location Of Hp3mentioning

confidence: 99%

“…Four subtypes of the a , subunit have been isolated, one Ntype VDCC (Williams et al, 1992a) and three L-type VDCC (Seino et al, 1992;Soldatov, 1992;Schultz et al, 1993).…”

mentioning

confidence: 99%

Cloning, chromosomal location and functional expression of the human voltage‐dependent calcium‐channel β3 subunit

Collin

Lory

Taviaux

et al. 1994

European Journal of Biochemistry

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“…The first set of oligonucleotides (forward primers) carrying the desired bases had at least 15 nucleotides on either side of the mutation and had the sequence GTG GCC CTC CTG ATC TTC ATG CTG TTC TTC ATC; CTC CTG ATC GTG ATG GTG TTC TTC ATC TAC GCG; CTG ATC GTG ATG CTG ATG TTC ATC TAC GCG GTG; CCC TAT GTG GCC CTC CTG CTC TTC CTG GTG TTC TTC ATC TAC GCG for V1339F, L1341V, F1342M, and HHT-5421, respectively. The reverse primer GGT TGA TGA TCA GGA AGG C was designed around the BclI site (4311) of hHT-1 (14). PCR was performed on the hHT-1 template using in each reaction one mutant primer and a BclI primer.…”

Section: Methodsmentioning

confidence: 99%

“…The wild type and mutant ␣ 1C (14) messages were co-injected in a 50-nl solution composed of ␣ 2 /␦ (2, 17) and human ␤ 3 (15,18) subunits in a 2:1:1 molar ratio. Ca 2ϩ channel currents were recorded 2-4 days postinjection of the cRNAs at room temperature (20 -21°C).…”

Section: Methodsmentioning

confidence: 99%

The Role of Region IVS5 of the Human Cardiac Calcium Channel in Establishing Inactivated Channel Conformation

Bódi¹,

Koch²,

Yamaguchi³

et al. 2002

Journal of Biological Chemistry

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The role of inactivated channel conformation and use dependence for diltiazem, a specific benzothiazepine calcium channel inhibitor, was studied in chimeric constructs and point mutants created in the IVS5 transmembrane segment of the L-type cardiac calcium channel. All mutations, chimeric or point mutations, were restricted to IVS5, while the YAI-containing segment in IVS6, i.e. the primary interaction site with benzothiazepines, remained intact. Slowed inactivation rate and incomplete steady state inactivation, a behavior of some mutants, were accompanied by a reduced or by a complete loss of use-dependent block by diltiazem. L-type Ca 2ϩ channels of cardiac, skeletal, and smooth muscle play a central role in excitation-contraction coupling. It is also believed that these channels may participate in the pathophysiology of some cardiac arrhythmias, hypertension, and angina pectoris (1-4). Increases in [Ca 2ϩ ] i have been linked to a variety of changes in membrane properties that contribute to the changes in excitability, conduction, refractoriness, automaticity, and vascular resistance (1-4). In terms of excitation-contraction coupling, Ca 2ϩ enters the cell during depolarization through voltage-activated calcium channels and triggers contraction but also is responsible for activation of other cellular functions. In the course of sustained depolarization, Ca 2ϩ currents progressively undergo voltage-dependent inactivation with specific kinetics, primarily regulated by the membrane potential.Ca 2ϩ channels are the target for three main classes of drugs that include dihydropyridines (DHP), 1 phenylalkylamines (PAA), and benzothiazepines (BTZ). These molecules bind specifically to different sites of the Ca 2ϩ channel ␣ 1 subunit, and their binding domains are allosterically linked to each other (5-7). Ca 2ϩ channel antagonists, particularly diltiazem and verapamil, block calcium channels in a voltage-and use-dependent manner; thus the binding of the drug facilitates protein conformational changes that alter channel function by interfering with channel gating. These drugs serve as useful tools in dissecting molecular mechanisms of channel inactivation. Several amino acid residues that are involved in Ca 2ϩ antagonist binding, when mutated, change the electrophysiological properties of the channel, such as voltage-dependent inactivation. Single amino acids in segments IIIS6 and IVS6 (5, 8 -11) have been identified as determinants of inactivation. Mutation of key amino acids in these segments alters not only the high affinity drug-binding sites but also the complexity of the kinetic behavior of the channels, consequently changing use-dependent block particularly for the PAAs and BTZs (for review, see Ref. 12).Our previous finding showed that a segment in IVS5 of the human ␣ 1C (Ca v 1.2) subunit is critically involved in inactivation of the channel (13). Consequently, mutants constructed in this region lost the characteristic use-dependent block by PAA and BTZ and recovered from inactivation significantly faster a...

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“…Over the past decades, some arrhythmic susceptible genes, including voltage-gated L-type calcium channel (LTCC), have been identified many arrhythmia-associated mutations [3–5]. LTCC is the main pathway for calcium ion influx into excitable cells in response to the membrane depolarization [6,7], which forms one part of cardiomyocyte action potentials (APs). In the heart, LTCC is a multi-subunit protein complex composed by four subunits: α 1 subunit and auxiliary β, α 2 δ and γ subunits, encoded by CACNA1C or CACNA1D, CACNB2, CACNA2D and CACNG , respectively [8,9].…”

Section: Introductionmentioning

confidence: 99%

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

et al. 2018

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The voltage-gated L-type calcium channel (LTCC) is essential for multiple cellular processes. In the heart, calcium influx through LTCC plays an important role in cardiac electrical excitation. Mutations in LTCC genes, including CACNA1C, CACNA1D, CACNB2 and CACNA2D, will induce the dysfunctions of calcium channels, which result in the abnormal excitations of cardiomyocytes, and finally lead to cardiac arrhythmias. Nevertheless, the newly found mutations in LTCC and their functions are continuously being elucidated. This review summarizes recent findings on the mutations of LTCC, which are associated with long QT syndromes, Timothy syndromes, Brugada syndromes, short QT syndromes, and some other cardiac arrhythmias. Indeed, we describe the gain/loss-of-functions of these mutations in LTCC, which can give an explanation for the phenotypes of cardiac arrhythmias. Moreover, we present several challenges in the field at present, and propose some diagnostic or therapeutic approaches to these mutation-associated cardiac diseases in the future.

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Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart.

Cited by 118 publications

References 23 publications

Cloning, chromosomal location and functional expression of the human voltage‐dependent calcium‐channel β3 subunit

Cloning, chromosomal location and functional expression of the human voltage‐dependent calcium‐channel β3 subunit

The Role of Region IVS5 of the Human Cardiac Calcium Channel in Establishing Inactivated Channel Conformation

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

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