Inhibition of annexin V-dependent Ca2+ movement in large unilamellar vesicles by K201, a new 1,4-benzothiazepine derivative

Kaneko, Noboru; Matsuda, Ryuko; Toda, Masashi; Shimamoto, Ken

doi:10.1016/s0005-2736(97)00132-6

Cited by 52 publications

(31 citation statements)

References 25 publications

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“…The 1,4-benzothiazepine derivative K-201, a specific annexin Ca 2ϩ channel blocker (19,20,31), inhibited Ca 2ϩ influx into liposomes mediated by annexin II, V, or VI in a dose-dependent manner (Fig. 2).…”

Section: Resultsmentioning

confidence: 94%

The Roles of Annexins and Types II and X Collagen in Matrix Vesicle-mediated Mineralization of Growth Plate Cartilage

Kirsch

Harrison

Golub

et al. 2000

Journal of Biological Chemistry

193

187

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Annexins II, V, and VI are major components of matrix vesicles (MV), i.e. particles that have the critical role of initiating the mineralization process in skeletal tissues. Furthermore, types II and X collagen are associated with MV, and these interactions mediated by annexin V stimulate Ca 2؉ uptake and mineralization of MV. However, the exact roles of annexin II, V, and VI and the interaction between annexin V and types II and X collagen in MV function and initiation of mineralization are not well understood. Annexins are a family of proteins that has in common the ability to bind to acidic phospholipids in the presence of Ca 2ϩ (1, 2). The family consists of at least 12 members, and three of them, annexins II, V, and VI, are highly expressed in calcifying cartilage and bone (3, 4). Annexin II and V each contain four 70 -80 amino acids repeats with an annexin consensus sequence. Annexin VI contains eight such repeats. These four or eight repeats form the conserved core region, which is responsible for the Ca 2ϩ -dependent binding of the proteins to phospholipids. In contrast, the N-terminal regions of the annexins are highly variable and may contribute to the specific functions of the various annexins (1, 2).Annexins II, V, and VI are major components of matrix vesicles (MV), 1 which are particles that, after being released from the plasma membrane of hypertrophic chondrocytes or osteoblasts, have the critical role of initiating the mineralization process in cartilage and perhaps in bone (3, 5). Three independent lines of evidence indicate that annexin II, V, and VI exhibit distinct Ca 2ϩ ion channel properties. First, when inserted into artificial phosphatidylserine bilayers they form voltage-dependent Ca 2ϩ ion channels (6 -8). Second, the crystal structures of these annexins are largely ␣-helical with parallel barrels of ␣-helical domains forming a hydrophilic, charged pore through the center of the protein (6, 8, 9). Third, annexin II, V, and VI are able to mediate Ca 2ϩ influx into artificial liposomes (10;11). It was shown that annexin-mediated Ca 2ϩ influx into liposomes is rapid during the first 20 min and then reaches a plateau after 20 min (10, 11).The initial phase of MV-mediated mineralization is characterized by the uptake of mineral ions by these particles and the formation and growth of the first mineral phase inside the vesicles (5). Because MV are enclosed by a membrane, channel proteins are required to mediate the influx of mineral ions into these particles. Previous findings from our and other laboratories, showed that chymotrypsin treatment, which removes most of the annexins from MV, and zinc treatment, which inhibits annexin-mediated Ca 2ϩ influx into phosphatidylserine (PS)-enriched liposomes, diminished MV Ca 2ϩ uptake (12-15), suggesting that annexins II, V, and VI serve as ion channels in MV, enabling Ca 2ϩ loading of the vesicles during the initial phase of mineralization.Previous studies have revealed that collagen types II and X are associated with the outer surface of MV (16). We...

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Section: Resultsmentioning

confidence: 94%

The Roles of Annexins and Types II and X Collagen in Matrix Vesicle-mediated Mineralization of Growth Plate Cartilage

Kirsch

Harrison

Golub

et al. 2000

Journal of Biological Chemistry

193

187

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“…The drug inhibited the myo®brillar overcontraction induced by high extracellular Ca 2+ combined with epinephrine and/ or ca eine (Kaneko, 1994). Kaneko et al (1997) ascribed the cardioprotective e ect to the inhibitory e ect on annexin V. More recently Inagaki, et al (2000) have demonstrated that JTV-519 activates speci®cally d-isoform of protein kinese C through a receptor-independent mechanism and thereby induces pharmacological preconditioning. They concluded that the cardioprotective e ect of JTV-519 cannot be attributed to the Ca 2+ channel blocking action although the drug inhibited the L-type Ca 2+ current (I Ca ) in concentrations higher than 1 mM (Kimura et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts

Nakaya

Furusawa

Ogura

et al. 2000

British J Pharmacology

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We investigated the effects of JTV‐519 (4‐[3‐(4‐benzylpiperidin‐1‐yl)propionyl]‐7‐methoxy‐2,3,4,5‐tetrahydro‐1,4‐benzothiazepine monohydrochloride), a novel cardioprotective drug, on the repolarizing K+ currents in guinea‐pig atrial cells by use of patch‐clamp techniques. We also evaluated the effects of JTV‐519 on experimental atrial fibrillation (AF) in isolated guinea‐pig hearts. In atrial cells stimulated at 0.2 Hz, JTV‐519 in concentrations of 0.3 and 1 μM slightly prolonged the action potential duration (APD). The drug also reversed the action potential shortening induced by the muscarinic agonist carbachol in a concentration‐dependent manner. The muscarinic acetylcholine receptor‐operated K+ current (IK.ACh) was activated by the extracellular application of carbachol (1 μM), adenosine (10 μM) or by the intracellular loading of GTPγS (100 μM). JTV‐519 inhibited the carbachol‐, adenosine‐ and GTPγS‐induced IK.ACh with the IC50 values of 0.12, 2.29 and 2.42 μM, respectively, suggesting that the drug may inhibit IK.ACh mainly by blocking the muscarinic receptors. JTV‐519 (1 μM) inhibited the delayed rectifier K+ current (IK). Electrophysiological analyses indicated that the drug preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component). In isolated hearts, perfusion of carbachol (1 μM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold (AFT). Addition of JTV‐519 (1 μM) inhibited the induction of AF by prolonging MAP and ERP. We conclude that JTV‐519 can exert antiarrhythmic effects against AF by inhibiting repolarizing K+ currents. The drug may be useful for the treatment of AF in patients with ischaemic heart disease. British Journal of Pharmacology (2000) 131, 1363–1372; doi:10.1038/sj.bjp.0703713

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“…JTV-519 (K201), a 1,4-benzothiazepine, was noted to have effects on intracellular Ca 2+ (35) and cardioprotective effects (36). However, the target was not known and there was no mechanism of action for JTV-519.…”

Section: Fixing Leaky Ryr2 Channelsmentioning

confidence: 99%

Calcium cycling proteins and heart failure: mechanisms and therapeutics

Marks¹

2013

J. Clin. Invest.

332

290

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Ca 2+ -dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca 2+ cycling refers to the release and reuptake of intracellular Ca 2+ that drives muscle contraction and relaxation. In failing hearts, Ca 2+ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca 2+ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca 2+ storage organelle in muscle. Defects in the regulation of Ca 2+ cycling proteins including the ryanodine receptor 2, cardiac (RyR2)/ Ca 2+ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a)/phospholamban complex contribute to heart failure. RyR2s are oxidized, nitrosylated, and PKA hyperphosphorylated, resulting in "leaky" channels in failing hearts. These leaky RyR2s contribute to depletion of Ca 2+ from the SR, and the leaking Ca 2+ depolarizes cardiomyocytes and triggers fatal arrhythmias. SERCA2a is downregulated and phospholamban is hypophosphorylated in failing hearts, resulting in impaired SR Ca 2+ reuptake that conspires with leaky RyR2 to deplete SR Ca 2+ . Two new therapeutic strategies for heart failure (HF) are now being tested in clinical trials: (a) fixing the leak in RyR2 channels with a novel class of Ca 2+ -release channel stabilizers called Rycals and (b) increasing expression of SERCA2a to improve SR Ca 2+ reuptake with viral-mediated gene therapy. There are many potential opportunities for additional mechanism-based therapeutics involving the machinery that regulates Ca 2+ cycling in the heart. Excitation-contraction couplingWith each beat of the heart, Ca 2+ is released from the sarcoplasmic reticulum (SR) via the ryanodine receptor 2, cardiac (RyR2), raising the cytosolic Ca 2+ concentration about ten-fold (∼1 μM) and activating cardiac muscle contraction (Figure 1). The Ca 2+ is then pumped back into the SR by the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a), lowering the cytosolic Ca 2+ concentration to baseline levels (∼100 nM) and causing relaxation. The Ca 2+ release and reuptake cycle is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and the specialized invagination called the transverse tubule (T tubule). Voltage-gated Ca 2+ channels on the T tubule are activated by depolarization and allow a small amount of Ca 2+ to run down its concentration gradient from mM external Ca 2+ concentration to nM internal Ca 2+ concentration. This entering Ca 2+ binds to and activates RyR2 channels, which release Ca 2+ stored at high concentration (in the millimolar range) in the SR. The Ca 2+ binds to troponin C, allowing actin-myosin cross-bridging and the thick and thin filaments of the sarcomere to slide past each other, shortening the sarcomere and causing cardiac muscle contraction. Heart failureHeart failure (HF) is the leading cause of mortality and morbidity in developed countries. The incidence of HF continues to increase a...

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Inhibition of annexin V-dependent Ca2+ movement in large unilamellar vesicles by K201, a new 1,4-benzothiazepine derivative

Cited by 52 publications

References 25 publications

The Roles of Annexins and Types II and X Collagen in Matrix Vesicle-mediated Mineralization of Growth Plate Cartilage

The Roles of Annexins and Types II and X Collagen in Matrix Vesicle-mediated Mineralization of Growth Plate Cartilage

Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts

Calcium cycling proteins and heart failure: mechanisms and therapeutics

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