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Terrance P. Snutch - One of the best experts on this subject based on the ideXlab platform.
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advances in voltage gated Calcium Channel structure function and physiology
Biochimica et Biophysica Acta, 2013Co-Authors: Gerald W. Zamponi, Terrance P. SnutchAbstract:It is well established that Calcium ions are important signalling molecules that mediate a wide range of physiological functions, including muscle contraction, enzyme activation, and secretion. Excitable cells contain numerous pathways by which intracellular Calcium concentration can be elevated. Voltage-gated Calcium Channels are the primary mechanism of depolarization evoked Calcium entry into heart, muscle and brain cells. The mammalian genome expresses multiple Calcium Channel subtypes that fulfill specific cellular functions. These Calcium Channels can either be monomers (as is the case with low voltage- activated T-type Calcium Channels), or multimeric protein complexes that are formed through the assembly of multiple Calcium Channels subunits (as for the high voltage-activated Calcium Channels). This special issue of BBA Biomembranes, focuses on some of the key roles of Calcium Channels, as well as aspects of Calcium Channel structure and modulation. In the lead off article, Dr. Diane Lipscombe discusses the role of alternate splicing in Calcium Channel function. Most Calcium Channel subtypes are subject to regulation by alternate splicing mechanisms, and the resulting splice variants support specific cellular functions. Dr. Jiang Yang then describes the regulation of high voltage-activated Calcium Channels by the ancillary Cavβ subunit. This subunit associates with the pore forming Cavα1 subunit of the Channel complex to not only regulate plasma membrane expression, but also Channel function and modulation. Along these lines, Dr. Annette Dolphin discusses the role of the other major high voltage-activated Calcium Channel ancillary subunit – Cavα2δ – in membrane trafficking of the Channel complex, and as a target for the gabapentinoid pain therapeutics. Dr. Jin Tao then focuses on low voltage activated T-type Calcium Channels and their modulation by second messengers. T-type Calcium Channels play major roles in network synchrony and epilepsy as discussed byDrs.Hee-SupShinandSnutchintwoarticlesinthisissue. Inaddition, there is growing evidence that T-type Channels mal also control low threshold exocytosis, as described by Drs. Norbert Weiss and Zamponi. Dr. Kurt Beam leads off a series of articles concerning the Cav1 (L-type) Calcium Channel family. Dr. Beam summarizes the unique functioning of the skeletal muscle Cav1.1L-type Channel. Dr. Alexandra Koschak then discusses how naturally occurring mutation in the Cav1 family provides novel insights into Calcium Channel structure and function. Rounding out the L-type Channel segment, Dr. Emilio Carbone focuses on the roles of Cav1.2 and Cav1.3 Calcium Channels in chromaffin cells. The issue then moves towards N-type (Cav2.2) Calcium Channels. Dr. Adams provides a detailed overview of modulation of N-type Calcium Channels by peptide toxins isolated from fish hunting cone snails, and their therapeutic potential for chronic pain. Drs. Kevin Currie and Zamponi then provide a detailed account concerning the modulation of N-type Calcium Channels by G proteins and G protein coupled receptors, a field of long history and an example of deep insights into molecular mechanisms of Channel modulation. Dr. Henry Colecraft takes a broader view of high voltage activated Calcium Channel modulation by RGK proteins, a family of small G proteins that mediate a complex regulation of Calcium Channel activity. Finally, Dr. Daniela Pietrobon completes the issue by highlighting the role of Cav2.1 (P/Q-type) Calcium Channels in familial forms of migraine. In patients with this disorder naturally occurring mutations in the P/Q-type gene give rise to migraine phenotypes with varying degrees of severity. Clearly, this collection of reviews is only a snapshot of the many exciting findings in the Calcium Channel field. However, it provides a topical overview of pertinent topics in this area by some of the world's leading Calcium Channel researchers.
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Scaffold-based design and synthesis of potent N-type Calcium Channel blockers.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Gerald W. Zamponi, Hassan Pajouhesh, Zhong Ping Feng, Lingyun Zhang, Yanbing Ding, Francesco Belardetti, David Dolphin, Lester A. Mitscher, Terrance P. SnutchAbstract:The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion Channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type Calcium Channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type Calcium Channel blockers which have good selectivity over L-type Calcium Channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium Channel.
Kevin P Campbell - One of the best experts on this subject based on the ideXlab platform.
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cloning and tissue specific expression of the brain Calcium Channel β subunit
FEBS Letters, 1991Co-Authors: Marlon Pragnell, Junshi Sakamoto, Scott David Jay, Kevin P CampbellAbstract:A cDNA clone encoding a protein with high homology to the β-subunit of the rabbit skeletal muscle dihydropyridine-sensitive Calcium Channel was isolated from a rat brain cDNA library. This rat brain β-subunit cDNA hybridizes to a 3.4 kb message that is expressed in high levels in the cerebral hemispheres and hippocampus but is significantly reduced in cerebellum. The open reading frame encodes 597 amino acids with a predicted mass of 65 679 Da which is 82% homologous with the skeletal muscle β-subunit. The brain cDNA encodes a unique 153 amino acid C-terminus and predicts the absence of a muscle-specific 50 amino acid internal segment. It also encodes numerous consensus phosphorylation sites suggesting a role in Calcium Channel regulation. The corresponding human β-subunit gene was localized to chromosome 17. Hence the encoded brain β-Subunit. which has a primary structure highly similar to its isoform in skeletal muscle, may have a comparable role as an integral regulatory component of a neuronal Calcium Channel.
Gerald W. Zamponi - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and pharmacological evaluation of some substituted dihydropyrimidines with l t type Calcium Channel blocking activities
Bioorganic Chemistry, 2019Co-Authors: Mohamed Teleb, Gerald W. Zamponi, Ola H Rizk, Fangxiong Zhang, Frank R Fronczek, Hesham FahmyAbstract:New dihydropyrimidines bearing various lipophilic pharmacophores and functionalities at position 3 were designed and synthesized. The basic framework of the new compounds was designed to maintain the main structural requirements for Calcium Channel blocking activity of the known dihydropyridines and dihydropyrimidines Calcium Channel blockers. The newly synthesized compounds were evaluated as antagonists for CaV1.2 and CaV3.2 using the whole-cell patch clamp technique. Seven compounds (4b, 4c, 6c, 9, 13c, 13e and 17b) showed promising dual Calcium Channel blocking activity and three compounds (13b, 14b and 17a) were selective against Cav3.2. Their drug-likeness has been assessed using Molinspiration and Molsoft softwares. Their physicochemical properties and pharmacokinetic profiles recommend that they can be considered as drug-like candidates.
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advances in voltage gated Calcium Channel structure function and physiology
Biochimica et Biophysica Acta, 2013Co-Authors: Gerald W. Zamponi, Terrance P. SnutchAbstract:It is well established that Calcium ions are important signalling molecules that mediate a wide range of physiological functions, including muscle contraction, enzyme activation, and secretion. Excitable cells contain numerous pathways by which intracellular Calcium concentration can be elevated. Voltage-gated Calcium Channels are the primary mechanism of depolarization evoked Calcium entry into heart, muscle and brain cells. The mammalian genome expresses multiple Calcium Channel subtypes that fulfill specific cellular functions. These Calcium Channels can either be monomers (as is the case with low voltage- activated T-type Calcium Channels), or multimeric protein complexes that are formed through the assembly of multiple Calcium Channels subunits (as for the high voltage-activated Calcium Channels). This special issue of BBA Biomembranes, focuses on some of the key roles of Calcium Channels, as well as aspects of Calcium Channel structure and modulation. In the lead off article, Dr. Diane Lipscombe discusses the role of alternate splicing in Calcium Channel function. Most Calcium Channel subtypes are subject to regulation by alternate splicing mechanisms, and the resulting splice variants support specific cellular functions. Dr. Jiang Yang then describes the regulation of high voltage-activated Calcium Channels by the ancillary Cavβ subunit. This subunit associates with the pore forming Cavα1 subunit of the Channel complex to not only regulate plasma membrane expression, but also Channel function and modulation. Along these lines, Dr. Annette Dolphin discusses the role of the other major high voltage-activated Calcium Channel ancillary subunit – Cavα2δ – in membrane trafficking of the Channel complex, and as a target for the gabapentinoid pain therapeutics. Dr. Jin Tao then focuses on low voltage activated T-type Calcium Channels and their modulation by second messengers. T-type Calcium Channels play major roles in network synchrony and epilepsy as discussed byDrs.Hee-SupShinandSnutchintwoarticlesinthisissue. Inaddition, there is growing evidence that T-type Channels mal also control low threshold exocytosis, as described by Drs. Norbert Weiss and Zamponi. Dr. Kurt Beam leads off a series of articles concerning the Cav1 (L-type) Calcium Channel family. Dr. Beam summarizes the unique functioning of the skeletal muscle Cav1.1L-type Channel. Dr. Alexandra Koschak then discusses how naturally occurring mutation in the Cav1 family provides novel insights into Calcium Channel structure and function. Rounding out the L-type Channel segment, Dr. Emilio Carbone focuses on the roles of Cav1.2 and Cav1.3 Calcium Channels in chromaffin cells. The issue then moves towards N-type (Cav2.2) Calcium Channels. Dr. Adams provides a detailed overview of modulation of N-type Calcium Channels by peptide toxins isolated from fish hunting cone snails, and their therapeutic potential for chronic pain. Drs. Kevin Currie and Zamponi then provide a detailed account concerning the modulation of N-type Calcium Channels by G proteins and G protein coupled receptors, a field of long history and an example of deep insights into molecular mechanisms of Channel modulation. Dr. Henry Colecraft takes a broader view of high voltage activated Calcium Channel modulation by RGK proteins, a family of small G proteins that mediate a complex regulation of Calcium Channel activity. Finally, Dr. Daniela Pietrobon completes the issue by highlighting the role of Cav2.1 (P/Q-type) Calcium Channels in familial forms of migraine. In patients with this disorder naturally occurring mutations in the P/Q-type gene give rise to migraine phenotypes with varying degrees of severity. Clearly, this collection of reviews is only a snapshot of the many exciting findings in the Calcium Channel field. However, it provides a topical overview of pertinent topics in this area by some of the world's leading Calcium Channel researchers.
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Scaffold-based design and synthesis of potent N-type Calcium Channel blockers.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Gerald W. Zamponi, Hassan Pajouhesh, Zhong Ping Feng, Lingyun Zhang, Yanbing Ding, Francesco Belardetti, David Dolphin, Lester A. Mitscher, Terrance P. SnutchAbstract:The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion Channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type Calcium Channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type Calcium Channel blockers which have good selectivity over L-type Calcium Channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium Channel.
Franz Hofmann - One of the best experts on this subject based on the ideXlab platform.
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expression of t and l type Calcium Channel mrna in murine sinoatrial node
FEBS Letters, 2000Co-Authors: Georg Bohn, Franz Hofmann, Sven Moosmang, Heinke Conrad, Andreas Ludwig, Norbert KlugbauerAbstract:At the cellular level, cardiac pacemaking which sets the rate and rhythm of the heartbeat is produced by the slow diastolic depolarization. Several ion Channels contribute to this pacemaker depolarization, including T-type and L-type Calcium currents. To evaluate the molecular basis of the currents involved, we investigated the cellular distribution of various low voltage activated (LVA) and high voltage activated (HVA) Calcium Channel mRNAs in the murine sinoatrial (SA) node by in-situ hybridization. The most prominently expressed LVA Calcium Channel in the SA node is Cav3.1, whereas Cav3.2 is present at moderate levels. The dominant HVA Calcium Channel transcript is Cav1.2; only traces of Cav1.3 mRNA are detectable in SA myocytes of mice.
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requirement of the Calcium Channel β subunit for functional conformation
FEBS Letters, 1993Co-Authors: Seiichiro Nishimura, Franz Hofmann, Veit Flockerzi, Hiroshi Takeshima, Keiji ImotoAbstract:Abstract The cardiac dihydropyridine-sensitive L-type Calcium Channel was stably expressed in Chinese hamster ovary cells by transfecting the rabbit cardiac Calcium Channel α1 subunit cDNA with or without coexpression of the β subunit of skeletal muscle Calcium Channel. Whereas coexpression of the β subunit significantly increased DHP binding activity and Calcium Channel activity, it did not affect the amount of the α1 subunit expressed, as judged by RNA blot hybridization analysis and immunoblotting analysis. The results suggest that association with the β subunit is necessary for the α1 subunit protein to take a proper conformation suitable for a functional Calcium Channel.
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primary structure and functional expression from complementary dna of a brain Calcium Channel
Nature, 1991Co-Authors: Yasuo Mori, Atsushi Mikami, Thomas Friedrich, Junichi Nakai, Peter Ruth, Eva Bosse, Franz Hofmann, Veit Flockerzi, Teiichi Furuichi, Katsuhiko MikoshibaAbstract:The primary structure of a voltage-dependent cal-cium Channel from rabbit brain has been deduced by cloning and sequencing the complementary DNA. Calcium Channel activity expressed from the cDNA is dramatically increased by coexpression of the α2 and β subunits, known to be associated with the dihydropyridine receptor. This Channel is a high voltage-activated Calcium Channel that is insensitive both to nifedipine and to ω-conotoxin. We suggest that it is expressed predominantly in cerebellar Purkinje cells and granule cells.
şukru Beydemir - One of the best experts on this subject based on the ideXlab platform.
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anti diabetic properties of Calcium Channel blockers inhibition effects on aldose reductase enzyme activity
Applied Biochemistry and Biotechnology, 2019Co-Authors: Cuneyt Turkes, Yeliz Demir, şukru BeydemirAbstract:Aldose reductase (AR) belongs to NADPH-dependent oxidoreductases and converts glucose to sorbitol in the polyol pathway. AR inhibition is essential to prevent diabetic complications. Here, AR was purified from sheep kidney using simple methods and determined the interactions between some Calcium Channel blockers and the enzyme. It was found that Calcium Channel blockers (cinnarizine, nilvadipine, amlodipine besylate, nifedipine, isradipine, and nitrendipine) exhibit potential inhibitor properties for sheep kidney AR with IC50 values in the range of 5.87–8.77 μM and Ki constants in the range of 2.07 ± 0.72–5.62 ± 1.53 μM. The Calcium Channel blockers showed different inhibition mechanisms. It was determined that all studied compounds showed competitive inhibition effect except for isradipine and nitrendipine. They showed non-competitive inhibition. Among these drugs, cinnarizine was found to be the most potent AR inhibitor (Ki: 2.07 ± 0.72 μM). They may be useful in the treatment and/or prevention of diabetic complications.
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effect of Calcium Channel blockers on paraoxonase 1 pon1 activity and oxidative stress
Pharmacological Reports, 2014Co-Authors: Cuneyt Turkes, Hakan Soyut, şukru BeydemirAbstract:Abstract Background In this study, we investigated the in vitro effects of Calcium Channel blockers (nifedipine, nitrendipine, isradipine, and amlodipine besylate) on the activity of paraoxonase-1 (PON1). Methods PON1 was purified from human serum using simple chromatographic methods, including DEAE-Sephadex anion-exchange and Sephadex G-200 gel filtration chromatography. Results The Calcium Channel blockers decreased the in vitro PON1 activity. The inhibition mechanism of amlodipine besylate was noncompetitive, whereas nifedipine, nitrendipine, and isradipine were competitive inhibitors. Conclusions Our results showed that Calcium Channel blockers exhibit inhibitory effects on PON1 at low concentrations. The IC 50 values for nifedipine, nitrendipine, isradipine, and amlodipine besylate were determined to be 0.121 mM, 0.130 mM, 0.255 mM, and 0.304 mM, respectively, and the K i constants were calculated to be 0.222 ± 0.049 mM, 0.151 ± 0.067 mM, 0.286 ± 0.137 mM, and 0.321 ± 0.002 mM, respectively.