Cloning and Characterization of 1H From Human Heart, a Member of the T-Type Ca²⁺ Channel Gene Family

From the Department of Physiology (L.L.C., J.-H.L., J.Y., A.D., E.P.-R.) and the Cardiovascular Institute (L.L.C., E.P.-R.), Loyola University Medical Center, Maywood, Ill; the Department of Physiology (J.S., Y.Z.), University of Kentucky, Lexington, Ky; the Department of Paediatrics (J.B., M.P.W., M.R.), The Rayne Institute, University College London Medical School, London, UK; and the MRC Human Biochemical Genetics Unit (M.F.), The Galton Laboratory, London, UK.

Correspondence to Leanne L. Cribbs, Department of Physiology, Loyola University Medical Center, 2160 South First Ave, Maywood, IL 60153. E-mail lcribbs{at}luc.edu

	Abstract

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Abstract—Voltage-activated Ca²⁺ channels exist as multigene families that share common structural features. Different Ca²⁺ channels are distinguished by their electrophysiology and pharmacology and can be classified as either low or high voltage–activated channels. Six 1 subunit genes cloned previously code for high voltage–activated Ca²⁺ channels; therefore, we have used a database search strategy to identify new Ca²⁺ channel genes, possibly including low voltage–activated (T-type) channels. A novel expressed sequence–tagged cDNA clone of 1G was used to screen a cDNA library, and in the present study, we report the cloning of 1H (or Ca_vT.2), a low voltage–activated Ca²⁺ channel from human heart. Northern blots of human mRNA detected more 1H expression in peripheral tissues, such as kidney and heart, than in brain. We mapped the gene, CACNA1H, to human chromosome 16p13.3 and mouse chromosome 17. Expression of 1H in HEK-293 cells resulted in Ca²⁺ channel currents displaying voltage dependence, kinetics, and unitary conductance characteristic of native T-type Ca²⁺ channels. The 1H channel is sensitive to mibefradil, a nondihydropyridine Ca²⁺ channel blocker, with an IC₅₀ of 1.4 µmol/L, consistent with the reported potency of mibefradil for T-type Ca²⁺ channels. Together with 1G, a rat brain T-type Ca²⁺ channel also cloned in our laboratory, these genes define a unique family of Ca²⁺ channels.

Key Words: T-type Ca²⁺ channel • 1 subunit • cloning • mibefradil

	Introduction

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Molecular cloning has revealed that the main pore-forming (1) subunits of voltage-gated ion channels are encoded by a large family of related genes. The 1 subunit consists of 4 homologous repeats (I to IV), each having 6 transmembrane segments (S1 to S6) containing a highly conserved pore loop and a distinctive voltage sensor (S4). HVA Ca²⁺ channels can be classified by their pharmacological properties into L, N, P, Q, and R types. Previously, 6 Ca²⁺ channel 1 subunit genes have been isolated (1S, 1C, 1D, 1A, 1B, and 1E), and all of these code for HVA channels.¹

LVA T-type Ca²⁺ channels were first discovered in the mid 1980s in cells isolated from dorsal root ganglion,^{2 3 4 5} in cardiac myocytes,^{6 7} and in pituitary GH3 cells.⁸ In contrast to the HVA class, T-type channels have a distinctive voltage dependence, fast inactivation resulting in "transient" currents, and a small (tiny) single-channel conductance with Ba²⁺ as the charge carrier.⁶ T-type Ca²⁺ channels are also relatively resistant to agents that block HVA channels.

T-type Ca²⁺ channels in the cardiovascular system may function in pacemaker activity,^{9 10} and abnormal expression of T-type channels has been observed in some animal models of hypertrophy¹¹ and hypertension.¹² The widely used therapeutic Ca²⁺ channel antagonists, such as diltiazem, verapamil, and nifedipine, are L-type channel blockers; these drugs are used extensively to treat hypertension and angina.¹³ L-type channels are widespread in the cardiovascular system, in cardiac myocytes, and in coronary smooth muscle. In the normal heart, T-type Ca²⁺ channels are more restricted to conduction tissues, such as atrial pacemaker cells and Purkinje fibers, but are also found in coronary smooth muscle.^{14 15 16} Recently, a new class of nondihydropyridine Ca²⁺ channel antagonists has been developed; they are structurally and functionally different from L-type channel blockers, with unique actions likely due to relative selectivity for T-type channels. Mibefradil (Hoffman-La Roche, Inc) is the first of these drugs currently used as an alternative medication for hypertension and angina pectoris.

We have cloned a novel Ca²⁺ channel from human heart, 1H. When expressed in HEK-293 cells, the 1H cDNA results in currents characteristic of native T-type channels. 1H is the second member identified of a new family of T-type Ca²⁺ channels. Finally, we demonstrated that the 1H channel is sensitive to mibefradil, with an IC₅₀ of 1.4 µmol/L, in agreement with the relative selectivity of this drug for T-type Ca²⁺ channels reported previously.^{17 18 19}

	Materials and Methods

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Genetic databases were searched using a text-based strategy, specifically looking for sequences similar to Ca²⁺ channels. Expressed sequence-tagged clones were obtained from Genome Systems, Inc. For probes, cDNA clones were radioactively labeled using the RadPrime kit (GIBCO-BRL) and [-³²P]dCTP from Amersham. A human heart cDNA library in gt10 was screened by conventional filter hybridization according to the manufacturer's protocol (Clontech). The 1H coding sequence was assembled in the EcoRI-KpnI sites of the vector pSP72 (Promega) by standard methods as follows: cDNA clone hhD1 (EcoRI [-74] to BamHI [725]) was ligated with clone hh4 (BamHI [725] to BspEI [2627]), clone hh12-1 (BspEI [2627] to SalI [4621]), and hh22-1 (SalI [4624] to KpnI [7461]). The 1H cDNA was sequenced on both strands using oligonucleotide primers and Sequenase v. 2.0 (Amersham). Sequence data acquisition, comparison, and alignments were performed using a digitizer and DNASIS for Windows software (Hitachi).

The human chromosomal location of the CACNA1H gene was determined using the Genbridge 4 radiation hybrid panel and a PCR assay (forward primer, 5'-TCGTGCGCAAAGTATCTGTG-3'; reverse primer, 5'-TGCCGGCCCCATAGGTCTC-3'). Fluorescent in situ hybridization of the CACNA1H cDNA clone hh19-2 (4734 to 7758) to 20 normal male human metaphase spreads was carried out as described previously.^{20 21} The mouse chromosomal location of Cacna1h was determined using the EUCIB backcross panel.²² A PCR assay based on the sequence of Genbank No. W76774 (Genbank No. AF051947) (forward primer, 5'-AGATGGATGCCGAGATCGAG-3'; reverse primer, 5'-CACAGATACTTTGCGCACGA-3') and a Mus spretus–specific MspI polymorphism were used.

A human multiple-tissue Northern blot was obtained from Clontech and hybridized at 42°C for 16 to 20 hours in a solution containing 50% formamide according to the manufacturer's protocol. An 1H cDNA probe (nucleotides 3962 to 5664) was added at a concentration of 2x10⁶ cpm/mL. The blot was washed up to 60°C in a final buffer of 0.1x SSC (15 mmol/L NaCl and 1.5 mmol/L sodium citrate) plus 0.1% SDS.

For expression in mammalian cells, the 1H sequence (-74 to 7461) was cloned into the EcoRV-XbaI sites of the transfection vector pcDNA3 (Invitrogen), resulting in 1H-Tx. HEK-293 cells (1x10⁵ per 35-mm dish) were transfected using the CalPhos Maximizer kit (Clontech) with 2 µg of 1H-Tx plasmid, with the addition of 1 µg pHook-2 (Invitrogen) in some cases. Transiently transfected cells were selected for expression of pHook by adherence of Capture-tec beads (Invitrogen) before electrophysiological experiments. For comparison, we used a HEK-293 stable cell line transfected with 1C,²³ 2,²⁴ and ß2A.²⁵ Each subunit was transfected and selected separately using the resistance markers for neomycin (1C), hygromycin (2), and zeomycin (ß2A) (Invitrogen).

Whole-cell recording was performed, with Ba²⁺ used as the charge carrier, by the ruptured-patch method in a solution containing (mmol/L) BaCl₂ 10, TEA-Cl 140, CsCl 6, and HEPES 10 (pH 7.4 adjusted with TEA-OH). The internal pipette solution contained (mmol/L) CsCl 55, CsSO₄ 75, MgCl₂ 10, EGTA 0.1, and HEPES 10 (pH adjusted to 7.2 with CsOH). Currents were recorded using an Axopatch 200A amplifier, a Digidata 1200 A/D converter, and pCLAMP software (Axon Instruments, Inc). Data were digitized at 2 kHz and filtered at 1 kHz. Pipettes were pulled from TW-150-6 capillary tubing (World Precision Instruments) and fire-polished. Tip resistance was between 1.7 and 3 M. Current amplitudes and exponential fits (Chebyshev method) were calculated using Clampfit software (Axon Instruments, Inc). Prism software (Graphpad) was used to fit data with either Boltzmann or sigmoidal dose-response equations. Pooled data are expressed as mean±SEM.

For single-channel analysis, HEK-293 cells were cotransfected with 1H-Tx and a plasmid coding for GFP (green fluorescent protein, "pS65T," a gift from T. McClintock, University of Kentucky, Lexington). Fluorescent cells were patch-clamped in the cell-attached configuration. In a separate series of experiments, we confirmed that all cells with green fluorescence also expressed 1H using the whole-cell recording mode. Single channels were measured with standard depolarizing bath solution containing (mmol/L) KCl 140, EGTA 10, MgCl₂ 1, CaCl₂ 1, dextrose 10, and HEPES 10 (pH 7.4), and the pipette solution contained (mmol/L) BaCl₂ 115, EGTA 1, and HEPES 10 (pH 7.4). The data were low pass–filtered at 2 kHz and digitized at 10 kHz under control of pClamp6 acquisition software (Axon Instruments). For off-line analysis, data were digitally filtered at 1 kHz. Data analysis was performed with the ChAnal program (Webfoot Software, courtesy of D. Piper, University of Utah, Salt Lake City). Single-channel amplitudes were estimated with the variance-mean technique to allow for discrimination of small amplitude events.²⁶

	Results

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In an effort to find potential T-type Ca²⁺ channel sequences that escaped previous detection by homology-based screening methods, we searched the Genbank databases for sequences similar to cloned Ca²⁺ channels and identified multiple cDNA clones that were unique. One partial expressed sequence–tagged cDNA sequence from clone H06096 was similar to the first membrane-spanning region (S1) of domain III of the carp 1S (Genbank No. P22316). We determined the full sequence of H06096 (Genbank No. AF029228) and found that it contained a putative voltage sensor and pore loop characteristic of voltage-activated ion channels and then used it as a probe to screen a human heart cDNA library. Successive rounds of screening resulted in 4 overlapping cDNAs encoding the full-length sequence of 1H, or Ca_vT.2 (Genbank accession No. AF051946).

This cDNA predicts a protein of 2042 amino acids with the overall structure of a voltage-gated Ca²⁺ channel. Searching the nonredundant Genbank database sequences showed highest homology of 1H with a protein predicted from the genomic DNA of the nematode Caenorhabditis elegans, C54D2.5 (Genbank No. U37548). Additional database sequences of mouse and human origin were homologous with 1H and are likely to be members of the same class of Ca²⁺ channels.

Figure 1 shows an alignment of 1H versus 1G, a T-type Ca²⁺ channel from rat brain also isolated in our laboratory.²⁷ Both sequences predict a 4-domain structure with conserved pore loops (P loop) and voltage sensors (S4), which are defining features of voltage-gated ion channels. It is interesting that in domains III and IV of both novel channels, the negatively charged glutamates involved in Ca²⁺ selectivity,²⁸ which are invariant in all the HVA Ca²⁺ channels, are replaced by aspartates. The amino acid sequence of 1H has an overall sequence identity of 57% with 1G; allowing for conservative substitutions with respect to structure shows that these proteins are 70% similar. Much higher sequence identity (average, 90%) is found in the putative transmembrane segments. The amino and carboxyl termini and the cytoplasmic interdomain loops are most divergent, although some small stretches of homology exist. The lack of an identifiable motif for binding of the ß subunits²⁹ suggests that these channels do not interact with the same ß subunits that are important for HVA channel function.³⁰ Ca²⁺ binding domains that play a role in Ca²⁺-dependent inactivation³¹ are also absent. Careful comparison of the expressed properties of 1H with other Ca²⁺ channels is needed to explore the functional relevance of these sequence differences.

View larger version (71K): [in this window] [in a new window]   Figure 1. Alignment of the deduced amino acid sequences of 1H and 1G, a T-type Ca2+ channel cDNA isolated in our laboratory27 (Genbank accession No. AF027984). Membrane-spanning segments are marked (S1 through S6), along with the pore loops (P loop) in each domain. Amino acids are color coded as follows: positively charged residues are red, negatively charged residues are green, neutral polar residues are blue, and neutral nonpolar residues are yellow.

The homology analysis shown in Figure 2 demonstrates that the HVA channels (grouped into L-type versus non–L-type) are separated from a less homologous class of channels that contains 1G and 1H. The high level of divergence between the HVA and LVA classes of Ca²⁺ channels explains why previous screening techniques based on homology failed to reveal these novel genes.

View larger version (14K): [in this window] [in a new window]   Figure 2. Homology analysis of Ca2+ channel sequences. Membrane-spanning regions, as marked in Figure 1, were compared for all the cloned Ca2+ channel types. The Genbank accession numbers of sequences compared are as follows: 1S, M23919; 1C, L04569; 1D, M76558; 1A, X99897; 1B, M94172; and 1E, L27745.

The human CACNA1H locus, corresponding to 1H, was assigned to chromosome 16 between the markers WI-7742 and WI-3061 with a LOD (logarithm for the likelihood of linkage) score of >3. A chromosomal band location of 16p13.3 was assigned by fluorescent in situ hybridization analysis. The mouse Cacna1h locus was mapped to mouse chromosome 17 between the markers D17Mit55 and D17Mit100, at a distance of 7.5 cM from the centromere with a LOD score of 8.0. This is a previously defined conserved linkage group.³² No mouse or human phenotypes have been mapped to these chromosomal regions so far. These data confirm the separate identity of 1H and 1G, since CACNA1G (corresponding to the 1G cDNA) was mapped to human chromosome 17q22 and mouse chromosome 11.²⁷

Figure 3 shows a Northern blot of human tissues using sequences from domains III and IV of 1H (nucleotides 3962 to 5664) as a probe. The high abundance of the 1H transcript (7.9 kb) in kidney was consistent on multiple independent blots (not shown) and may reflect a role for this T-type channel in kidney that warrants further study. Another consistent finding is the relatively higher abundance of 1H in heart over brain. When probes derived from 1G were used on the same or comparable blots, the ratio of signal in brain versus heart was higher,²⁷ indicating that 1G and 1H are enriched in their respective source tissues.

View larger version (81K): [in this window] [in a new window]   Figure 3. Distribution of 1H in human tissues. A human multiple-tissue Northern blot was probed with 1H (nucleotides 3962 to 5664) and exposed for 23 days. Molecular weight markers are indicated on the right in kilobases.

We tested for functional expression of the 1H cDNA by transfecting the full-length coding sequence into HEK-293 cells. Figure 4 shows representative whole-cell current traces elicited by depolarizing pulses in 10 mmol/L Ba²⁺ for 1H (panel A) compared with a HEK-293 cell stably transfected with 1C from rabbit heart (panel B). Corresponding current-voltage relationships are compared in Figure 4C, displaying an activation threshold around -60 mV for 1H compared with -30 mV for 1C. These data were transformed into conductance and then fit with the Boltzmann equation to calculate the midpoint of activation (V_0.5) of -44±0.3 mV with a slope factor (k) of 7.2±0.3 (n=9) for 1H (Figure 4D) compared with V_0.5 of -3±1.5 mV with a k value of 6.6±1.4 (n=6) for 1C. Inactivation of the 1H channel was measured after 5-second prepulses to approximate steady-state conditions, occurring at subthreshold potentials (V_0.5=-75.3±0.3, k=-7.8±0.3, n=8).

View larger version (30K): [in this window] [in a new window]   Figure 4. Expression of 1H in transfected HEK-293 cells. Whole-cell currents were recorded using the ruptured-patch method with 10 mmol/L Ba2+ as the charge carrier. A, Currents recorded from cells transfected with 1H. B, Currents recorded from cells stably transfected with 1C for comparison. C, Average current-voltage curves from 1H () and 1C (), both measured in the same solution. Error bars represent the SEM from n=9 (1H) or n=6 (1C) cells. D, Voltage dependence of inactivation (n=8) and activation (n=9) for 1H. Activation, or chord conductance (Gmax), was calculated by dividing the peak current measured during each test potential by the driving force. Inactivation was measured by assaying for channel availability after 5-second prepulses. Smooth curves represent Boltzmann fits to the data.

Kinetic analysis of 1H currents is shown in Figure 5. Inward Ba²⁺ currents activated slowly near threshold potentials, whereas stronger depolarizations produced a current that activated and inactivated quickly (Figure 5A and 5B). These kinetics are defining features of T-type channels.¹⁹ Another characteristic of T-type Ca²⁺ channels is their slow deactivation (tail current) after a test pulse.⁸ The time and voltage dependence of deactivation is illustrated in Figure 5C and 5D. The voltage dependence of tail deactivation follows that previously demonstrated for native T-type tail currents.⁸

View larger version (25K): [in this window] [in a new window]   Figure 5. Kinetic properties and deactivation of 1H currents. A and B, Voltage dependence values for time constants (tau) of activation (A) and inactivation (B) are shown for 1H. Data represent the mean±SD from 6 cells. C, 1H tail currents were elicited by a voltage protocol, including a 10-millisecond step to -20 mV followed by repolarization to various potentials. D, Data in panel C were fit with a single exponential and then plotted as a function of the repolarization potential. Data are the mean±SD from 7 cells.

T-type Ca²⁺ channels are defined by a small (<9 pS) unitary conductance in Ba²⁺ solutions.^{2 6} We exploited the slow tail current kinetics to measure unitary events under conditions of greater driving force (Figure 6A). The main conductance level of 1H was 5.3±0.3 pS (n=5) in 115 mmol/L external Ba²⁺ (Figure 6C). This value is in the range of previous reports of T-type channels in native preparations. Opening and closing to subconductance levels were also observed. For repolarization potentials negative to -40 mV, most single-channel events occurred within the initial 10 milliseconds after repolarization. However, an exceptionally long opening is shown for -80 mV. This occurred only once in 200 sweeps but is useful for illustrating single-channel amplitude. The ensemble averages (Figure 6B) were fit with a single exponential. Similar to whole-cell macroscopic current, the time constant for decay was more rapid at more negative repolarization potentials (data not shown).

View larger version (19K): [in this window] [in a new window]   Figure 6. Single-channel measurements of 1H. A, Single channels measured using a tail current protocol to measure current at greater driving force than with a single-step depolarization. Protocol shown above currents included a step to +30 mV for 10 milliseconds with a return to various test potentials (Vtest). Representative currents are shown during repolarization Vtest values to -40, -60, and -80 mV. There were >3 channels in this patch. Dashed lines indicate openings to the most frequent amplitude level. B, Ensemble-averaged current from 264 sweeps at Vtest of -60 mV. The smooth curve is a single exponential fit with a time constant of 4.1 milliseconds. C, Single-channel current voltage curve fitted with conductance of 5.3 pS (n=5).

Since mibefradil has previously been reported to be selective for T-type Ca²⁺ channels,^{17 18} we tested mibefradil block of 1H channels in transfected HEK-293 cells. Figure 7A shows that 1 µmol/L mibefradil caused 50% block of the 1H currents; the dose-response curve shown in Figure 7B resulted in an IC₅₀ of 1.4 µmol/L.

View larger version (11K): [in this window] [in a new window]   Figure 7. Mibefradil block of 1H in HEK-293 cells. A, Currents evoked during test pulses to –30 mV in the absence and presence of increasing concentrations of mibefradil. Currents were evoked every 15 seconds from a holding potential of –90 mV. B, Dose-response analysis of mibefradil block. Inhibition of peak currents was normalized to control and then plotted as a function of drug concentration. The smooth curve was generated from a fit to the data (n=6) with a sigmoidal dose-response equation (Hill slope=1.1).

	Discussion

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We have demonstrated that 1H, cloned from human heart, is an LVA T-type Ca²⁺ channel. The present study, in conjunction with a previous report,²⁷ defines a new family of Ca²⁺ channels separate from the cloned HVA genes. The genomic sequence of a third homologous gene found on human chromosome 22 was reported in the Genbank (accession No. AL008716).³³ We refer to this gene as CACNA1I and its putative product as 1I.³⁴ Two of the 3 family members identified so far, 1G and 1H, have been demonstrated to be T-type Ca²⁺ channels on the basis of their expression in heterologous systems.²⁷ We include 1I as a member of this family on the basis of its sequence similarity with 1G and 1H (80% for the membrane-spanning portions); however, its properties can only be established by measuring its expression.

The genes encoding 1G and 1H are localized on different chromosomes, and each has a unique pattern of tissue distribution. Both 1G and 1H are expressed in heart and brain, and Northern blots reveal that their relative levels differ between the 2 tissues. The significance of the multiple genes with respect to tissue or cell type is not yet known. For example, previous electrophysiological measurements from normal cardiac cells have localized T-type currents to pacemaker cells,^{9 10} and additional studies are needed to determine which gene(s) mediates those currents. Also, the high abundance of 1H in kidney was not seen for 1G, perhaps indicating a functional difference for these 2 channels.

Mibefradil has previously been shown to be a selective blocker of T-type Ca²⁺ channels.^{17 18} We obtained an IC₅₀ of 1.4 µmol/L, which is in the range of previous reported values (ranging from 100 nmol/L in vascular smooth muscle to 2.7 µmol/L in neuroblastoma cells).^{17 18} L-type channels under similar conditions are roughly 10-fold less sensitive to mibefradil. Although differences in reported sensitivities to mibefradil and other blockers could depend on the conditions used, we suggest that some of the variability may arise from the expression of different members of the T-type Ca²⁺ channel gene family. We are now in a position to test this hypothesis with the recombinant T-type Ca²⁺ channels.

The identification of multiple genes encoding T-type Ca²⁺ channels is a significant advance in the study of voltage-gated ion channels. The availability of recombinant T-type channels makes it possible to study T-type currents without interference from contaminating L-type currents often present in cell preparations. This will lead to a better understanding of their pharmacological and biophysical properties. These genes will also provide a tool for exploring the underlying molecular basis for the diverse properties of T-type currents observed in different cell preparations and aid in the discovery of important T-type–specific therapeutic agents.

	Selected Abbreviations and Acronyms

 

HVA = high voltage–activated LVA = low voltage–activated PCR = polymerase chain reaction TEA = tetraethylammonium

	Acknowledgments

 
This study was supported by grants from the National Institutes of Health, Potts Foundation, and the Medical Research Council. Dr Perez-Reyes is an Established Investigator of the American Heart Association. We thank the UK HGMP Resource Center for the Genbridge 4 radiation hybrid mapping panel and the EUCIB mouse panel.

Received February 24, 1998; accepted May 14, 1998.

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				K. Talavera, M. Staes, A. Janssens, N. Klugbauer, G. Droogmans, F. Hofmann, and B. Nilius Aspartate Residues of the Glu-Glu-Asp-Asp (EEDD) Pore Locus Control Selectivity and Permeation of the T-type Ca2+ Channel alpha 1G J. Biol. Chem., November 30, 2001; 276(49): 45628 - 45635. [Abstract] [Full Text] [PDF]

				J. C. Gomora, A. N. Daud, M. Weiergraber, and E. Perez-Reyes Block of Cloned Human T-Type Calcium Channels by Succinimide Antiepileptic Drugs Mol. Pharmacol., November 1, 2001; 60(5): 1121 - 1132. [Abstract] [Full Text] [PDF]

				O. Lesouhaitier, A. Chiappe, and M. F. Rossier Aldosterone Increases T-Type Calcium Currents in Human Adrenocarcinoma (H295R) Cells by Inducing Channel Expression Endocrinology, October 1, 2001; 142(10): 4320 - 4330. [Abstract] [Full Text] [PDF]

				L. L. Cribbs Vascular Smooth Muscle Calcium Channels: Could "T" Be a Target? Circ. Res., September 28, 2001; 89(7): 560 - 562. [Full Text] [PDF]

				S. M. Todorovic, V. Jevtovic-Todorovic, S. Mennerick, E. Perez-Reyes, and C. F. Zorumski Cav3.2 Channel Is a Molecular Substrate for Inhibition of T-Type Calcium Currents in Rat Sensory Neurons by Nitrous Oxide Mol. Pharmacol., September 1, 2001; 60(3): 603 - 610. [Abstract] [Full Text] [PDF]

				S. L. Lipsius, J. Huser, and L. A. Blatter Intracellular Ca2+ Release Sparks Atrial Pacemaker Activity Physiology, June 1, 2001; 16(3): 101 - 106. [Abstract] [Full Text] [PDF]

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				G.-Q. Xiao, K. Hu, and M. Boutjdir Direct Inhibition of Expressed Cardiac L- and T-Type Calcium Channels by IgG From Mothers Whose Children Have Congenital Heart Block Circulation, March 20, 2001; 103(11): 1599 - 1604. [Abstract] [Full Text] [PDF]

				L. L. Cribbs, B. L. Martin, E. A. Schroder, B. B. Keller, B. P. Delisle, and J. Satin Identification of the T-Type Calcium Channel (CaV3.1d) in Developing Mouse Heart Circ. Res., March 2, 2001; 88(4): 403 - 407. [Abstract] [Full Text] [PDF]

				A. D. Schrier, H. Wang, E. M. Talley, E. Perez-Reyes, and P. Q. Barrett {alpha}1H T-type Ca2+ channel is the predominant subtype expressed in bovine and rat zona glomerulosa Am J Physiol Cell Physiol, February 1, 2001; 280(2): C265 - C272. [Abstract] [Full Text] [PDF]

				M. Staes, K. Talavera, N. Klugbauer, J. Prenen, L. Lacinova, G. Droogmans, F. Hofmann, and B. Nilius The amino side of the C-terminus determines fast inactivation of the T-type calcium channel {alpha}1G J. Physiol., January 1, 2001; 530(1): 35 - 45. [Abstract] [Full Text] [PDF]

				M. Tateyama, S. Zong, T. Tanabe, and R. Ochi Properties of voltage-gated Ca2+ channels in rabbit ventricular myocytes expressing Ca2+ channel {alpha}1E cDNA Am J Physiol Cell Physiol, January 1, 2001; 280(1): C175 - C182. [Abstract] [Full Text] [PDF]

				S. M. Wilson, P. T. Toth, S. B. Oh, S. E. Gillard, S. Volsen, D. Ren, L. H. Philipson, E. C. Lee, C. F. Fletcher, L. Tessarollo, et al. The Status of Voltage-Dependent Calcium Channels in alpha 1E Knock-Out Mice J. Neurosci., December 1, 2000; 20(23): 8566 - 8571. [Abstract] [Full Text] [PDF]

				P. Q. Barrett, H.-K. Lu, R. Colbran, A. Czernik, and J. J. Pancrazio Stimulation of unitary T-type Ca2+ channel currents by calmodulin-dependent protein kinase II Am J Physiol Cell Physiol, December 1, 2000; 279(6): C1694 - C1703. [Abstract] [Full Text] [PDF]

				Y. Takagishi, K. Yasui, N. J. Severs, and Y. Murata Species-specific difference in distribution of voltage-gated L-type Ca2+ channels of cardiac myocytes Am J Physiol Cell Physiol, December 1, 2000; 279(6): C1963 - C1969. [Abstract] [Full Text] [PDF]

				R. C. Foehring, P. G. Mermelstein, W.-J. Song, S. Ulrich, and D. J. Surmeier Unique Properties of R-Type Calcium Currents in Neocortical and Neostriatal Neurons J Neurophysiol, November 1, 2000; 84(5): 2225 - 2236. [Abstract] [Full Text] [PDF]

				V. Leuranguer, A. Monteil, E. Bourinet, G. Dayanithi, and J. Nargeot T-type calcium currents in rat cardiomyocytes during postnatal development: contribution to hormone secretion Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2540 - H2548. [Abstract] [Full Text] [PDF]

				R. L. Martin, J.-H. Lee, L. L. Cribbs, E. Perez-Reyes, and D. A. Hanck Mibefradil Block of Cloned T-Type Calcium Channels J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 302 - 308. [Abstract] [Full Text]

				W.-Y. Son, J.-H. Lee, J.-H. Lee, and C.-T. Han Acrosome reaction of human spermatozoa is mainly mediated by {alpha}1H T-type calcium channels Mol. Hum. Reprod., October 1, 2000; 6(10): 893 - 897. [Abstract] [Full Text] [PDF]

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