Biomedical subjects

S Hering

Publications and source records attributed to S Hering.

At least 37 records · Page 2Linked to original sources

PubMed2001

Analysis of TGFbeta3 gene expression and protein levels in human bone and serum.

Recent data indicate that TGFbeta3, one member of the TGFbeta-isoforms, has an important role in bone remodeling. Up to date little is known about the expression and regulation of TGFbeta3 in man. We established a highly specific ELISA for quantitative measurement of TGFbeta3 in bone and blood samples and a RT-PCR in combination with HPLC for detection and quantification of TGFbeta3 mRNA in 89 human bone samples. Levels of TGFbeta3 protein ranged between 30 and 66 pg/mg bone (mean 36,6 +/-1,03 pg/mg) and between 30 and 1910 pg/ml in serum (mean 128.9+/-38.9 pg/ml). TGFbeta3 mRNA expression as well as protein levels in serum and in bone declined age dependently. No specific load- or site-specific distribution of TGFbeta3 mRNA expression or protein content was detected at different sites indicating an absence of mechanical regulation. Protein levels of TGFbeta3 in serum correlated with TGFbeta3 mRNA expression in bone (p= 0.0027; r=0.49). By contrast, TGFbeta3 protein levels stored in the bone matrix were not related to TGFbeta3 mRNA reflecting the long term process of TGFbeta3 deposition during bone remodeling. Notably TGFbeta3 serum levels were highly correlated with IGF-I and osteocalcin levels in serum. We conclude that TGFbeta3 in man circulates in significant amounts which appears to be representative for TGFbeta3 expression in bone tissue and may be in part derived from bone. The high correlation of TGFbeta3 with IGF-I suggests parallel systemic principles of regulation.

Adolescent↗

PubMed2001

Paraoxonase 1 192 Gln/Arg gene polymorphism and cerebrovascular disease: interaction with type 2 diabetes.

Paraoxonase 1 (PON1) is an HDL-associated enzyme which protects HDL and LDL particles from lipid peroxidation. Its enzymatic serum activity varies 10-40-fold between individuals, and its biallelic gene polymorphism at codon 192 (glutamine-->arginine, Gln/Arg) has been associated with coronary artery disease in diabetic patients. To evaluate the role of this PON1 gene polymorphism in cerebrovascular disease, we determined the PON1 192 genotype in 149 patients with hemodynamically relevant extracranial artery stenosis and in 241 controls. The PON1 192 Gln/Arg genotype was determined using polymerase chain reaction followed by Alw I digestion and polyacrylamide gel electrophoresis. Among all subjects, there was no association between the PON1 192 Gln/Arg genotype and cerebrovascular disease (Odds ratio for Arg/Arg and Gln/Arg vs Gln/Gln 0.99, 95%-CI 0.70-1.39). In contrast, in the subgroup of type 2 diabetic patients the PON1 192 Arg allele conferred about twice the risk of cerebrovascular stenosis compared to those homozygous for the Gln allele (Odds ratio 2.00, 95%-CI 0.92-4.38). Our data indicate that in the general population the PON1 192 Gln/Arg gene polymorphism cannot be regarded as a major risk marker for cerebrovascular disease. The observed interaction with type 2 diabetes, however, is supporting the hypothesis that the effect of the PON1 192 Arg allele on atherosclerosis is modulated by other risk factors like diabetes.

Aged↗

PubMed2001

TGFbeta1 and TGFbeta2 mRNA and protein expression in human bone samples.

Transforming growth factor beta is one of the most abundant growth factors stored in bone. It is known as a potent regulator of osteoblast proliferation and differentiation as well as of production extracellular matrix. We established a highly specific RT-PCR in combination with HPLC for detection and quantification of TGFbeta1 and TGFbeta2 mRNA expression in 89 human bone samples. Levels of TGFbeta1 protein ranged between 27 and 580 ng/g bone (mean 188 +/- 15 ng/g; n=75) and for TGFbeta2 between 7.2 and 35 ng/g bone (mean 14.3 +/- 2.1 ng/g; n=57). TGFbeta1 and TGFbeta2 protein concentrations and TGFbeta isoform mRNA expression in bone were not significantly different between the sexes. TGFbeta isoform mRNA expression as well as protein content in bone declined age dependently. TGFbeta1 and TGFbeta2 protein and mRNA expression were different in bone samples from different sites of the skeleton indicating in part the regulation by mechanical stimuli. In contrast to TGFbeta1, TGFbeta2 mRNA expression was significantly enhanced in osteoarthritic bone compared to unaffected bone. These data are in concordance to previous results concerning the expression of TGFbeta3 in bone. In conclusion, the data suggest distinct patterns' of expression of the TGFbeta isoforms under physiological and pathological conditions in bone.

Adolescent↗

PubMed2000

Molecular determinants of inactivation in voltage-gated Ca2+ channels.

Evolution has created a large family of different classes of voltage-gated Ca2+ channels and a variety of additional splice variants with different inactivation properties. Inactivation controls the amount of Ca2+ entry during an action potential and is, therefore, believed to play an important role in tissue-specific Ca2+ signalling. Furthermore, mutations in a neuronal Ca2+ channel (Ca(v)2.1) that are associated with the aetiology of neurological disorders such as familial hemiplegic migraine and ataxia cause significant changes in the process of channel inactivation. Ca2+ channels of a given subtype may inactivate by three different conformational changes: a fast and a slow voltage-dependent inactivation process and in some channel types by an additional Ca2+-dependent inactivation mechanism. Inactivation kinetics of Ca2+ channels are determined by the intrinsic properties of their pore-forming alpha1-subunits and by interactions with other channel subunits. This review focuses on structural determinants of Ca2+ channel inactivation in different parts of Ca2+ channel alpha1-subunits, including pore-forming transmembrane segments and loops, intracellular domain linkers and the carboxyl terminus. Inactivation is also affected by the interaction of the alpha1-subunits with auxiliary beta-subunits and intracellular regulator proteins. The evidence shows that pore-forming S6 segments and conformational changes in extra- (pore loop) and intracellular linkers connected to pore-forming segments may play a principal role in the modulation of Ca2+ channel inactivation. Structural concepts of Ca2+ channel inactivation are discussed.

Action Potentials↗

PubMed2000

Modulation of slow inactivation in class A Ca2+ channels by beta-subunits.

beta-subunit modulation of slow inactivation of class A calcium (Ca2+) channels was studied with two-microlectrode voltage clamp after expression of the alpha1A- (BI-2) together with beta1a-, beta2a-, beta3- or beta4-subunits in Xenopus oocytes. On- and off-rates of slow inactivation were estimated from the kinetics of recovery from slow inactivation. Ca2+ channels with an alpha1A/beta-subunit composition inducing the slower rate of fast inactivation displayed the faster rate of slow inactivation. The corresponding order of slow inactivation time constants (tau[onset]) was: alpha1A/beta2a, 33 +/- 3 s; alpha1A/beta4, 42 +/- 4 s; alpha1A/beta1a, 59 +/- 4 s; alpha1A/beta3, 67 +/- 5 s (n >= 7). Recovery of class A Ca2+ channels from slow inactivation was voltage dependent and accelerated at hyperpolarized voltages. At a given holding potential recovery kinetics were not significantly modulated by different beta-subunits. Two mutations in segment IIIS6 (IF1612/1613AA) slowed fast inactivation and accelerated the onset of slow inactivation in the resulting mutant (alpha1A/IF-AA/beta3) in a similar manner as coexpression of the beta2a-subunit. Recovery from slow inactivation was slightly slowed in the double mutant. Our data suggest that class A Ca2+ channels enter the 'slow inactivated' state more willingly from the open than from the 'fast inactivated' state. The rate of slow inactivation is, therefore, indirectly modulated by different beta-subunits. Fast and slow inactivation in class A Ca2+ channels appears to represent structurally independent conformational changes. Fast inactivation is not a prerequisite for slow inactivation.

Algorithms↗

PubMed2000

Mitochondrial DNA in the Central European population. Human identification with the help of the forensic mt-DNA D-loop-base database.

Sequencing of mtDNA is an advanced method for the individualisation of traces. Disadvantages of this method are expensive and time-consuming analysis and evaluation procedures as well as the necessary stock of population-genetic data which is still insufficient. Central European institutes of forensic medicine from Germany, Austria, and Switzerland have been working together since the beginning of 1998 to establish a mtDNA database. The aim is to build up a large stock of forensically established data and provide population-genetic data for frequency investigations, which will serve as a basis for expert opinions and scientific research. Good data quality is ensured by using original sequences only. Ring tests, which have been conducted to enhance analytical reliability, revealed a high correspondence rate of the analytical results obtained by the individual member institutes. Today 1410 sequences are available for comparison, of which 1285 sequences in the HV1 and HV2 regions cover the full ranges from 16051 to 16365 and from 73 to 340 (according to Anderson). The major part is formed by Central European sequences comprising 1256 data sets from Germany, Austria, and Switzerland. Today the database contains sequences from a total of 12 European, six African and three Asian countries including 100 sequences from Japan. This paper is aimed at discussing the individualisation potentials of mtDNA as well as the possibilities and limits of ethnic differentiation by means of pairwise sequence differences on the basis of the data stock available.

Austria↗

PubMed2000

Molecular mechanism of calcium channel block by isradipine. Role of a drug-induced inactivated channel conformation.

The role of the inactivated channel conformation in the molecular mechanism of Ca(2+) channel block by the 1,4-dihydropyridine (DHP) (+)-isradipine was analyzed in L-type channel constructs (alpha(1Lc); Berjukow, S., Gapp, F., Aczel, S., Sinnegger, M. J., Mitterdorfer, J., Glossmann, H., and Hering, S. (1999) J. Biol. Chem. 274, 6154-6160) and a DHP-sensitive class A Ca(2+) channel mutant (alpha(1A-DHP); Sinnegger, M. J., Wang, Z., Grabner, M., Hering, S., Striessnig, J., Glossmann, H., and Mitterdorfer, J. (1997) J. Biol. Chem. 272, 27686-27693) carrying the high affinity determinants of the DHP receptor site but inactivating at different rates. Ca(2+) channel inactivation was modulated by coexpressing the alpha(1A-DHP)- or alpha(1Lc)-subunits in Xenopus oocytes with either the beta(2a)- or the beta(1a)-subunit and amino acid substitutions in L-type segment IVS6 (I1497A, I1498A, and V1504A). Contrary to a modulated receptor mechanism assuming high affinity DHP binding to the inactivated state we observed no clear correlation between steady state inactivation and Ca(2+) channel block by (+)-isradipine: (i) a 3-fold larger fraction of alpha(1A-DHP)/beta(1a) channels in steady state inactivation at -80 mV (compared with alpha(1A-DHP)/beta(2a)) did not enhance the block by (+)-isradipine; (ii) different steady state inactivation of alpha(1Lc) mutants at -30 mV did not correlate with voltage-dependent channel block; and (iii) the midpoint-voltages of the inactivation curves of slowly inactivating L-type constructs and more rapidly inactivating alpha(1Lc)/beta(1a) channels were shifted to a comparable extent to more hyperpolarized voltages. A kinetic analysis of (+)-isradipine interaction with different L-type channel constructs revealed a drug-induced inactivated state. Entry and recovery from drug-induced inactivation are modulated by intrinsic inactivation determinants, suggesting a synergism between intrinsic inactivation and DHP block.

Animals↗

PubMed2000

High affinity interaction of mibefradil with voltage-gated calcium and sodium channels.

Mibefradil is a novel Ca(2+) antagonist which blocks both high-voltage activated and low voltage-activated Ca(2+) channels. Although L-type Ca(2+) channel block was demonstrated in functional experiments its molecular interaction with the channel has not yet been studied. We therefore investigated the binding of [(3)H]-mibefradil and a series of mibefradil analogues to L-type Ca(2+) channels in different tissues. [(3)H]-Mibefradil labelled a single class of high affinity sites on skeletal muscle L-type Ca(2+) channels (K(D) of 2.5+/-0.4 nM, B(max)=56.4+/-2.3 pmol mg(-1) of protein). Mibefradil (and a series of analogues) partially inhibited (+)-[(3)H]-isradipine binding to skeletal muscle membranes but stimulated binding to brain L-type Ca(2+) channels and alpha1C-subunits expressed in tsA201 cells indicating a tissue-specific, non-competitive interaction between the dihydropyridine and mibefradil binding domain. [(3)H]-Mibefradil also labelled a heterogenous population of high affinity sites in rabbit brain which was inhibited by a series of nonspecific Ca(2+) and Na(+)-channel blockers. Mibefradil and its analogue RO40-6040 had high affinity for neuronal voltage-gated Na(+)-channels as confirmed in binding (apparent K(i) values of 17 and 1.0 nM, respectively) and functional experiments (40% use-dependent inhibition of Na(+)-channel current by 1 microM mibefradil in GH3 cells). Our data demonstrate that mibefradil binds to voltage-gated L-type Ca(2+) channels with very high affinity and is also a potent blocker of voltage-gated neuronal Na(+)-channels. More lipophilic mibefradil analogues may possess neuroprotective properties like other nonselective Ca(2+)-/Na(+)-channel blockers.

Animals↗

PubMed2000

Analysis and simulation of wintertime light scattering by the urban aerosol in Dallas-Fort Worth.

Wintertime atmospheric light scattering in Dallas, TX, was estimated through the use of aerosol models. Input data for the aerosol models were provided by measurements of aerosol chemistry, physical particle size distributions, and distributions of particulate sulfur by particle size, and by predictions by an atmospheric simulation model. Light scattering measurements provided a basis for testing the aerosol models. The SCAPE thermodynamic equilibrium model was used to estimate the amount of liquid water associated with particles and the ELSIE Mie scattering model was applied to estimate the resulting light scattering. The calculations were based on aerosol properties measured in Dallas during December 1994 and February 1995, and changes in scattering due to hypothetical changes in the aerosol were predicted. The predicted light scattering was compared to scattering measured by an Optec nephelometer; agreement was within 20% in every case.

Aerosols↗

PubMed2000

Air quality measurements from the Fresno Supersite.

The Fresno Supersite intends to 1) evaluate non-routine monitoring methods, establishing their comparability with existing methods and their applicability to air quality planning, exposure assessment, and health effects studies; 2) provide a better understanding of aerosol characteristics, behavior, and sources to assist regulatory agencies in developing standards and strategies that protect public health; and 3) support studies that evaluate relationships between aerosol properties, co-factors, and observed health end-points. Supersite observables include in-situ, continuous, short-duration measurements of 1) PM2.5, PM10, and coarse (PM10 minus PM2.5) mass; 2) PM2.5 SO4(-2), NO3-, carbon, light absorption, and light extinction; 3) numbers of particles in discrete size bins ranging from 0.01 to approximately 10 microns; 4) criteria pollutant gases (O3, CO, NOx); 5) reactive gases (NO2, NOy, HNO3, peroxyacetyl nitrate [PAN], NH3); and 6) single particle characterization by time-of-flight mass spectrometry. Field sampling and laboratory analysis are applied for gaseous and particulate organic compounds (light hydrocarbons, heavy hydrocarbons, carbonyls, polycyclic aromatic hydrocarbons [PAH], and other semi-volatiles), and PM2.5 mass, elements, ions, and carbon. Observables common to other Supersites are 1) daily PM2.5 24-hr average mass with Federal Reference Method (FRM) samplers; 2) continuous hourly and 5-min average PM2.5 and PM10 mass with beta attenuation monitors (BAM) and tapered element oscillating microbalances (TEOM); 3) PM2.5 chemical speciation with a U.S. Environmental Protection Agency (EPA) speciation monitor and protocol; 4) coarse particle mass by dichotomous sampler and difference between PM10 and PM2.5 BAM and TEOM measurements; 5) coarse particle chemical composition; and 6) high sensitivity and time resolution scalar and vector wind speed, wind direction, temperature, relative humidity, barometric pressure, and solar radiation. The Fresno Supersite is coordinated with health and toxicological studies that will use these data in establishing relationships with asthma, other respiratory disease, and cardiovascular changes in human and animal subjects.

Aerosols↗

PubMed2000

Development of the X-linked tetrameric microsatellite marker DXS9898 for forensic purposes.

HumDXS9898 also known as CHLC x GATA 126G01 is a tetrameric microsatellite marker located at the Xq21.33 pericentromeric region. In kinship testing HumDXS9898 is suitable for concomitant use with HumHPRTB and HumDXS6807 which are separated from HumDXS9898 by genetic map distance of 150 and 80 cM, respectively. HumDXS9898 is closely linked to HumARA. In the German population, HumDXS9898 exhibits seven clearly distinguishable alleles ranging from 189 to 214 basepairs in size. Deviation from Hardy-Weinberg equilibrium could not be detected. The observed heterozygosity was 0.75 for females and the mean exclusion probability was 0.73 for female children. Mutations were not found in the present material.

DNA Fingerprinting↗

PubMed1999

Inactivation determinant in the I-II loop of the Ca2+ channel alpha1-subunit and beta-subunit interaction affect sensitivity for the phenylalkylamine (-)gallopamil.

1. The role of calcium (Ca2+) channel inactivation in the molecular mechanism of channel block by phenylalkylamines (PAAs) was analysed in a PAA-sensitive rabbit brain class A Ca2+ channel mutant (alpha1A-PAA). Use-dependent barium current (IBa) inhibition of alpha1A-PAA by (-)gallopamil and Ca2+ channel recovery from inactivation and block were studied with two-microlectrode voltage clamp after expression of alpha1A-PAA and auxiliary alpha2-delta- and beta1a- or beta2a-subunits in Xenopus oocytes. 2. Mutation Arg387Glu (alpha1A numbering) in the intracellular loop connecting domains I and II of alpha1A-PAA slowed the inactivation kinetics and reduced use-dependent inhibition (100 ms test pulses at 0.2 Hz from -80 to 20 mV) of the resulting mutant alpha1A-PAA/R-E/beta1a channels by 100 microM (-)gallopamil (53 +/- 2 %, alpha1A-PAA/beta1a vs. 31 +/- 2 %, alpha1A-PAA/R-E/beta1a, n >= 4). This amino acid substitution simultaneously accelerated the recovery of channels from inactivation and from block by (-)gallopamil. 3. Coexpression of alpha1A-PAA with the beta2a-subunit reduced fast IBa inactivation and induced a substantial reduction in use-dependent IBa inhibition by (-)gallopamil (25 +/- 4 %, alpha1A-PAA/beta2a; 13 +/- 1 %, alpha1A-PAA/R-E/beta2a). The time constant of recovery from block at rest was not significantly affected. 4. These results demonstrate that changes in channel inactivation induced by Arg387Glu or beta2a-alpha1-subunit interaction affect the drug-channel interaction.

Algorithms↗

PubMed1999

Sequence differences between alpha1C and alpha1S Ca2+ channel subunits reveal structural determinants of a guarded and modulated benzothiazepine receptor.

The molecular basis of the Ca2+ channel block by (+)-cis-diltiazem was studied in class A/L-type chimeras and mutant alpha1C-a Ca2+ channels. Chimeras consisted of either rabbit heart (alpha1C-a) or carp skeletal muscle (alpha1S) sequence in transmembrane segments IIIS6, IVS6, and adjacent S5-S6 linkers. Only chimeras containing sequences from alpha1C-a were efficiently blocked by (+)-cis-diltiazem, whereas the phenylalkylamine (-)-gallopamil efficiently blocked both constructs. Carp skeletal muscle and rabbit heart Ca2+ channel alpha1 subunits differ with respect to two nonconserved amino acids in segments IVS6. Transfer of a single leucine (Leu1383, located at the extracellular mouth of the pore) from IVS6 alpha1C-a to IVS6 of alpha1S significantly increased the (+)-cis-diltiazem sensitivity of the corresponding mutant L1383I. An analysis of the role of the two heterologous amino acids in a L-type alpha1 subunit revealed that corresponding amino acids in position 1487 (outer channel mouth) determine recovery of resting Ca2+ channels from block by (+)-cis-diltiazem. The second heterologous amino acid in position 1504 of segment IVS6 (inner channel mouth) was identified as crucial inactivation determinant of L-type Ca2+ channels. This residue simultaneously modulates drug binding during membrane depolarization. Our study provides the first evidence for a guarded and modulated benzothiazepine receptor on L-type channels.

Amino Acid Sequence↗

PubMed1998

Molecular mechanism of diltiazem interaction with L-type Ca2+ channels.

Benzothiazepine Ca2+ antagonists (such as (+)-cis-diltiazem) interact with transmembrane segments IIIS6 and IVS6 in the alpha1 subunit of L-type Ca2+ channels. We investigated the contribution of individual IIIS6 amino acid residues for diltiazem sensitivity by employing alanine scanning mutagenesis in a benzothiazepine-sensitive alpha1 subunit chimera (ALDIL) expressed in Xenopus laevis oocytes. The most dramatic decrease of block by 100 microM diltiazem (ALDIL 45 +/- 4.8% inhibition) during trains of 100-ms pulses (0.1 Hz, -80 mV holding potential) was found after mutation of adjacent IIIS6 residues Phe1164(21 +/- 3%) and Val1165 (8.5 +/- 1.4%). Diltiazem delayed current recovery by promoting a slowly recovering current component. This effect was similar in ALDIL and F1164A but largely prevented in V1165A. Both mutations slowed inactivation kinetics during a pulse. The reduced diltiazem block can therefore be explained by slowing of inactivation kinetics (F1164A and V1165A) and accelerated recovery from drug block (V1165A). The bulkier diltiazem derivative benziazem still efficiently blocked V1165A. From these functional and from additional radioligand binding studies with the dihydropyridine (+)-[3H]isradipine we propose a model in which Val1165 controls dissociation of the bound diltiazem molecule, and where bulky substituents on the basic nitrogen of diltiazem protrude toward the adjacent dihydropyridine binding domain.

Alanine↗

PubMed1998

Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics.

Missense mutations in the pore-forming human alpha1A subunit of neuronal P/Q-type Ca2+ channels are associated with familial hemiplegic migraine (FHM). The pathophysiological consequences of these mutations are unknown. We have introduced the four single mutations reported for the human alpha1A subunit into the conserved rabbit alpha1A (R192Q, T666M, V714A, and I1819L) and investigated possible changes in channel function after functional expression of mutant subunits in Xenopus laevis oocytes. Changes in channel gating were observed for mutants T666M, V714A, and I1819L but not for R192Q. Ba2+ current (IBa) inactivation was slightly faster in mutants T666M and V714A than in wild type. The time course of recovery from channel inactivation was slower than in wild type in T666M and accelerated in V714A and I1819L. As a consequence, accumulation of channel inactivation during a train of 1-Hz pulses was more pronounced for mutant T666M and less pronounced for V714A and I1819A. Our data demonstrate that three of the four FHM mutations, located at the putative channel pore, alter inactivation gating and provide a pathophysiological basis for the postulated neuronal instability in patients with FHM.

Animals↗

PubMed1998

TNFa and b microsatellites in Germany.

Allele frequencies of TNFa and TNFb microsatellites were determined from 315 healthy unrelated Germans (mothers and putative fathers) by means of PCR. They were stably inherited and segregated in a Mendelian way. New mutations were not observed.

Alleles↗

PubMed1998

Small-volume and rapid extracellular solution exchange around Xenopus oocytes during voltage-clamp recordings.

A novel method for micro extracellular perfusion of Xenopus oocytes has been designed in order to minimise the amount of test solution required for drug applications during two-microelectrode voltage-clamp experiments. Voltage-clamp experiments on oocytes are performed in a glass-covered microbath without continuous perfusion. The microelectrodes access the oocytes via two small openings in the glass cover. Test solutions are applied to a funnel at the chamber inflow and the chamber volume is subsequently exchanged by operating a suction pump connected to the chamber outflow. Only 50 microl of drug- or neurotransmitter-containing solution is required for bath application. In addition, the new "funnel application technique" enables quick and timed applications of drugs or neurotransmitters to Xenopus oocytes within 200-400 ms.

Acetylcholine↗

PubMed1998

Structural basis of drug binding to L Ca2+ channels.

At least five different types of voltage-gated Ca2+ channels exist in electrically excitable mammalian cells. Only one type, the family of L-type Ca2+ channels (L channels), contains high-affinity binding domains within their alpha 1-subunits for different chemical classes of drugs (Ca2+ channel antagonists; exemplified by isradipine, verapamil and diltiazem). Their stereoselective, high-affinity binding induces block of channel-mediated Ca2+ inward currents in heart and smooth muscle, resulting in antihypertensive, cardiodepressive and antiarrhythmic effects. Amino acids involved in drug binding have recently been identified using photoaffinity labelling, chimeric alpha 1-subunits and site-directed mutagenesis. Insertion of the drug-binding amino acids enabled the transfer of drug-sensitivity into Ca2+ channels that are insensitive to Ca2+ channel antagonists ('gain-of-function' approach). In this review, Jörg Striessing and colleagues summarize the present knowledge about the molecular architecture of L channel drug-binding domains and the implications for Ca2+ channel pharmacology and drug development.

Animals↗