Microtubule Disruption by Colchicine Reversibly Enhances Calcium Signaling in Intact Rat Cardiac Myocytes

Kerfant, Benoît-Gilles; Vassort, Guy; Gómez, Ana M.

doi:10.1161/hh0701.090462

Cited by 61 publications

(41 citation statements)

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“…Taxol stabilizes microtubles, thus blocking the dynamic process of polymerization and depolymerization needed for trafficking of macromolecules within the cell. Interestingly, Gomez and colleagues (19,20) reported that microtubule disruption with colchicine but not taxol affects I Ca,L in rat cardiac myocytes. We also found that colchicine, which causes microtubule depolymerization, increased I Ca,L density and blocked isoproterenol stimulation of I Ca,L in mouse myocytes (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Jiang

et al. 2007

Diabetes

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OBJECTIVE-Contraction of cardiac myocytes is initiated byCa 2ϩ entry through the voltage-dependent L-type Ca 2ϩ channel (LTCC). Previous studies have shown that phosphatidylinositol (PI) 3-kinase signaling modulates LTCC function. Because PI 3-kinases are key mediators of insulin action, we investigated whether LTCC function is affected in diabetic animals due to reduced PI 3-kinase signaling. RESEARCH DESIGN AND METHODS-We used whole-cell patch clamping and biochemical assays to compare cardiac LTCC function and PI 3-kinase signaling in insulin-deficient diabetic mice heterozygous for the Ins2 Akita mutation versus nondiabetic littermates.RESULTS-Diabetic mice had a cardiac contractility defect, reduced PI 3-kinase signaling in the heart, and decreased L-type Ca 2ϩ current (I Ca,L ) density in myocytes compared with control nondiabetic littermates. The lower I Ca,L density in myocytes from diabetic mice is due at least in part to reduced cell surface expression of the LTCC. I Ca,L density in myocytes from diabetic mice was increased to control levels by insulin treatment or intracellular infusion of PI 3,4,5-trisphosphate [PI(3,4,5)P 3 ]. This stimulatory effect was blocked by taxol, suggesting that PI(3,4,5)P 3 stimulates microtubule-dependent trafficking of the LTCC to the cell surface. The voltage dependence of steady-state activation and inactivation of I Ca,L was also shifted to more positive potentials in myocytes from diabetic versus nondiabetic animals. PI(3,4,5)P 3 infusion eliminated only the difference in voltage dependence of steady-state inactivation of I Ca,L .CONCLUSIONS-Decreased PI 3-kinase signaling in myocytes from type 1 diabetic mice leads to reduced Ca 2ϩ entry through the LTCC, which might contribute to the negative effect of diabetes on cardiac contractility. Diabetes 56:2780-2789, 2007 C ardiac complications are an important cause of morbidity and mortality in type 1 diabetic patients. This is partly due to the presence of hypertension and coronary artery disease, which are commonly associated with diabetes. Diabetes also increases the risk of developing cardiac dysfunction independently of these risk factors, supporting the existence of a distinct diabetic cardiomyopathy (1). A number of studies have shown that Ca 2ϩ entry through the voltagedependent L-type Ca 2ϩ channel (LTCC) is reduced in cardiac myocytes from streptozotocin-induced diabetic rats and from obese db/db mice, a well-known model of type 2 diabetes (2-5). This inward Ca 2ϩ current (I Ca,L ) is the critical initiator of the contractile cycle in cardiac myocytes, and inhibition of LTCC function would reduce Ca 2ϩ entry and contractile force. However, the molecular mechanism that underlies the LTCC defect in diabetic myocytes is unclear.Class I phosphatidylinositol (PI) 3-kinases preferentially phosphorylate PI 4,5-bisphosphate [PI(4,5)P 2 ] to form phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] in vivo and exhibit substantial activation in response to stimulation with insulin or other hormones. Studies in neuron...

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Section: Resultsmentioning

confidence: 99%

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Jiang

et al. 2007

Diabetes

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“…On the contrary, colchicine treatment occludes I K(ACh) activation by CCh. Also, microtubule disruption interferes with ␤-adrenoceptor regulation of excitation-contraction coupling (9,14). Thus microtubule depolymerization unmasks muscarinic signaling to L-type Ca 2ϩ channels and masks muscarinic signaling to I K(ACh) in rat ventricular myocytes.…”

Section: Discussionmentioning

confidence: 99%

“…]rest is initial intracellular Ca 2ϩ taken as 125 nM and Kd is the dissociation constant (400 nM) for Ca 2ϩ and fluo 3. To verify the microtubule disruption in our conditions, control and colchicine-treated myocytes were fixed and immunolabeled with anti ␤-tubulin as previously detailed (14). Images were recorded in the same microscope by using 2-photon excitation delivered by a Ti-Sa laser (Coherent) at 800 nm.…”

Section: Methodsmentioning

confidence: 99%

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Autonomic regulation of calcium and potassium channels is oppositely modulated by microtubules in cardiac myocytes

Gómez

Kerfant²,

Vassort³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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]i transients and contractions. Once Gi is activated by muscarinic agonist, the ␣ i-subunit is released from the ␤␥-subunits, but it is silent, and its inhibition of the AC/cAMP cascade, manifested by I Ca reduction, is not seen unless AC has been previously activated. In colchicine-treated cells, CCh caused greater reductions of [Ca 2ϩ ]i transients and contractions than in untreated cells. The ␣i-subunit became effective in signaling through the AC/cAMP cascade and reduced ICa without changing its voltage-dependence. Isoproterenol (Iso) regained its efficacy and reversed ICa inhibition by CCh. Stimulation of I Ca by forskolin persisted in colchicine-treated cells when Iso was ineffective. The effect of CCh on IK(ACh) was occluded in colchicine-treated cells. Colchicine treatment, per se, may increase I K(ACh) by ␤␥-subunits released from Gs to mask this effect of CCh. Microtubules suppress I Ca regulation by ␣i; their disruption releases restraints that unmask muscarinic inhibition of I Ca. Summarily, colchicine treatment reverses regulation of ventricular excitation-contraction coupling by autonomic agents.

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“…For example, perturbation of microtubule dynamics with depolymerizing or stabilizing agents inhibits skeletal myoblast fusion, differentiation, and normal myofibrillogenesis (Antin et al, 1981;Toyama et al, 1982;Saitoh et al, 1988). In the heart, disruption of microtubules alters cytoplasmic viscosity, myosin mRNA transport, Ca 2+ signaling, and gene expression (Perhonen et al, 1998;Takahashi et al, 1998;Gomez et al, 2000;Calaghan et al, 2001;Kerfant et al, 2001). Furthermore, microtubules are required for proper contractile function and their levels increase in animal models of pressure-overload cardiac hypertrophy (Klein, 1983;Tsutsui et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Muscle-specific RING finger-2 (MURF-2) is important for microtubule, intermediate filament and sarcomeric M-line maintenance in striated muscle development

McElhinny

Perry

Witt

et al. 2004

Journal of Cell Science

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The efficient functioning of striated muscle is dependent upon the structure of several cytoskeletal networks including myofibrils, microtubules, and intermediate filaments. However, little is known about how these networks function together during muscle differentiation and maintenance. In vitro studies suggest that members of the muscle-specific RING finger protein family (MURF-1, 2, and 3) act as cytoskeletal adaptors and signaling molecules by associating with myofibril components (including the giant protein, titin), microtubules and/or nuclear factors. We investigated the role of MURF-2, the least-characterized family member, in primary cultures of embryonic chick skeletal and cardiac myocytes. MURF-2 is detected as two species (∼55 kDa and ∼60 kDa) in embryonic muscle, which are down-regulated in adult muscle. Although predominantly located diffusely in the cytoplasm, MURF-2 also colocalizes with a sub-group of microtubules and the M-line region of titin. Reducing MURF-2 levels in cardiac myocytes using antisense oligonucleotides perturbed the structure of stable microtubule populations, the intermediate filament proteins desmin and vimentin, and the sarcomeric M-line region. In contrast, other sarcomeric regions and dynamic microtubules remained unaffected. MURF-2 knock-down studies in skeletal myoblasts also delayed myoblast fusion and myofibrillogenesis. Furthermore, contractile activity was also affected. We speculate that some of the roles of MURF-2 are modulated via titin-based mechanisms.

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Microtubule Disruption by Colchicine Reversibly Enhances Calcium Signaling in Intact Rat Cardiac Myocytes

Cited by 61 publications

References 50 publications

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Autonomic regulation of calcium and potassium channels is oppositely modulated by microtubules in cardiac myocytes

Muscle-specific RING finger-2 (MURF-2) is important for microtubule, intermediate filament and sarcomeric M-line maintenance in striated muscle development

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