Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.13.12.5 (aequorin)
 1,451 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the development of intracellular Ca2+ indicators, such as aequorin, fura-2 and indo-1, it became possible to examine the relationship between cytosolic Ca2+ levels ([Ca2+]i) and muscle contraction in various types of smooth muscles. In addition, the use of bacterial alpha-toxin and saponin, beta-escine, enabled us to make permeabilized muscle in which the receptor-coupled signal transduction system remains intact. Using these techniques, it was found that muscle contraction does not always parallel with [Ca2+]i. A typical example of such dissociation is seen in rat aorta which is classified as 'tonic muscle'; receptor agonists induce greater contraction than a high concentration of K+ at a given [Ca2+]i. Another example observed in a 'phasic muscle' of canine antrum is a temporal change in Ca2+ sensitivity; Ca2+ sensitivity initially increases and then decreases during the spontaneous rhythmic contractions. These results suggest that smooth muscle regulation is not explained solely by the classical Ca(2+)-dependent 'myosin phosphorylation theory'.
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PMID:Different Ca(2+)-sensitivity in phasic and tonic types of smooth muscles. 803 58

In vertebrate striated muscle, calcium binding to troponin initiates contraction, a strong interaction of actin and myosin. In isolated proteins and skinned fibers, the strong interaction of myosin with actin also affects troponin. Fluorescent labels attached to troponin C show structural changes in the TnC environment with cross-bridge attachment and also with calcium binding. Evidence that this effect of crossbridges also occurs in intact striated muscle comes from studies in partially activated cardiac or skeletal muscle by others and in barnacle muscle by us. Length changes which detach myosin cross-bridges produce a brief burst of extra calcium that can be detected by aequorin in activated, voltage clamped single barnacle muscle fibers. That this calcium is coming from calcium bound to the activating site (troponin-C) is supported by several pieces of evidence. Studies on the dependence of the extra calcium on force and the time of the length change are consistent with the amplitude of the extra calcium being proportional to the bound calcium (CaTnC) and with increased cross-bridge attachment and force increasing calcium binding to troponin-C by up to a factor of 10. Importantly, stretch of active muscle (which first detaches cross-bridges and then enhances steady force) gives a biphasic response: first extra calcium (presumably due to cross-bridge detachment) and then, decreased calcium (presumably due to enhanced calcium binding to TnC). The enhanced calcium binding we see with elevated force (via strained cross-bridges) implies that calcium binding to TnC is enhanced not only be cross-bridge attachment but also by crossbridge (or thin filament) strain. This effect of cross-bridge attachment/force on calcium binding is consistent with a dual mechanism of calcium activation of contraction. First, calcium binds to troponin in the thin filament activating strong myosin binding to the thin filament. Then, strong myosin binding in turn provides additional activation either by increasing calcium binding or by changing the thin filament structure directly allowing additional cross-bridge attachment.
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PMID:Cross-bridges affect both TnC structure and calcium affinity in muscle fibers. 810 32

To investigate postreceptor pathways of endothelin and the site of action responsible for enhancing myocardial contractility, studies were performed on ferret papillary muscles loaded with the Ca2+ indicator aequorin. Endothelin-1 (ET) and the alpha 1-adrenoceptor agonist, phenylephrine (PE) produced similar dose-dependent increases in tension development and peak intracellular Ca2+ concentration ([Ca2+]i); moreover, pretreatment with PE eliminated effects of ET, suggesting similar postreceptor pathways. Because alpha 1-adrenoceptor activation is thought to cause the hydrolysis of phosphatidylinositol and generate D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and 1,2-diacylglycerol (DAG), the protein kinase C (PKC) activator 4 beta-phorbol 12-myristate 13-acetate (PMA) was used to determine whether activation of PKC was responsible for the myocardial actions of ET. In contrast to ET, PMA decreased tension development and peak [Ca2+]i, and pretreatment with PMA attenuated the myocardial action of ET; however, intracellular Ins(1,4,5)P3 levels were greatly increased by ET stimulation, suggesting that rather than DAG, Ins(1,4,5)P3 might be the second messenger for the actions of ET. To determine whether ET produced actions on the contractile elements, thereby enhancing myocardial contractility, 2,3-butanedione monoxime (BDM) was used to interfere with the interaction of myosin and actin. Pretreatment with 6 mM BDM did not alter the half-maximum effective concentration (EC50) of the [Ca2+]o-tension relation, but, in contrast, shifted the ET dose-response curve to the right, and increased the EC50 by approximately 1.0 log unit. In addition, ET partially reversed the downward shift of the peak [Ca2+]i-peak tension curve induced by BDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelin-1 enhances cross-bridge function of ferret myocardium: role of second messengers. 828 56

Physiological and pharmacological interventions are used to regulate cardiac contractile functions via modulation of Ca2+ signaling. The relevant regulatory mechanisms have recently been assessed in detail by use of novel experimental procedures, which include simultaneous measurements of intracellular levels of Ca2+ ions and contractile force in intact myocardial preparations loaded with the intracellular Ca2+ indicator aequorin and fluorescent dyes, namely, fura-2, indo-1 and fluo-3. Association with or dissociation from intracellular Ca2+ transients of contractile activity is taken as evidence that reflects the primary mechanism of action of individual inotropic interventions. In addition, motility assays of actin-myosin interactions in vitro have made it possible to define the site of action of Ca2+ sensitizers as troponin C and the interaction of the troponin-tropomyosin complex with actin or the actin-myosin interface at crossbridges. Frank-Starling mechanism operates at the level of the binding of Ca2+ ions to troponin C and subsequent regulatory processes, while the force-frequency relationship is mainly ascribed to an alteration in the intracellular mobilization of Ca2+ ions. Cardiotonic agents can be classified as follows: 1) agents that act via a cyclic AMP-dependent or a cyclic AMP-independent mechanism; and 2) agents that facilitate the intracellular mobilization of Ca2+ ions or increase in myofibrillar sensitivity to Ca2+ ions. Regulatory mechanisms mediated via the phosphorylation of functional proteins induced by cyclic AMP, which is responsible for the actions of novel cardiotonic agents, beta 1-adrenoceptor partial agonist and selective inhibitors of phosphodiesterase (PDE) III, have currently been clarified in more detail. Ca2+ sensitizers are of extreme therapeutic interest because of their ability to increase myocardial contractility without an increase in activation energy; they are devoid of risks of arrhythmogenicity and myocardial cell death from intracellular Ca2+ overload; and they effectively reverse contractile dysfunction under pathophysiological situations, such as acidosis or myocardial stunning.
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PMID:Changes in intracellular Ca2+ mobilization and Ca2+ sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells. 960 80

Inotropic responsiveness to beta-adrenergic stimulation is generally found to be impaired in left ventricular (LV) hypertrophy and failure. To investigate the mechanisms by which angiotensin-converting enzyme inhibitor therapy may modulate inotropic responsiveness with long-term pressure overload, we studied the effects of captopril treatment on cardiac gene expression, LV muscle mechanical contraction, and intracellular calcium (Ca(2+)) transients from spontaneously hypertensive rats (SHR). LV papillary muscles from untreated SHR, age-matched normotensive Wistar-Kyoto rats (WKY), and SHR treated with captopril (CAP(Rx) started at 12, 18, and 21 months of age) were studied. All animals were studied at 24 months of age or when heart failure developed. In untreated SHR, alpha-myosin heavy chain (MHC) gene expression and protein were decreased, the Ca(2+) transient (with the bioluminescent indicator aequorin) was prolonged, and abundance of Na(+)/Ca(2+) exchanger mRNA levels increased in comparison to WKY. Active stress development at L(max) and the maximum rate of stress development were depressed and contractile duration prolonged in SHR relative to WKY. Isoproterenol administration further decreased active stress in untreated SHR despite an increase in intracellular Ca(2+) levels. In CAP(Rx) SHR, alpha-MHC gene expression and protein levels were increased, the Ca(2+) transient was not prolonged, Na(+)/Ca(2+) exchanger expression was downregulated, and papillary muscle function demonstrated increased active stress and maximum rate of stress development in response to isoproterenol. The increased abundance of alpha-MHC mRNA in conjunction with an increase in V(1) myosin isozyme suggests that captopril affects transcriptional regulation of cardiac gene expression. Restored LV inotropic responsiveness to beta-adrenergic stimulation in CAP(Rx) SHR appears to be coupled to normalization of Na(+)/Ca(2+) exchanger mRNA expression, upregulation of V(1) myosin isozyme levels, and increased speed of contraction.
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PMID:Altered inotropic responsiveness and gene expression of hypertrophied myocardium with captopril. 1085 64

X-ray diffraction studies were made using synchrotron radiation on ferret right ventricular papillary muscle under three different thyroid states: euthyroidism, hyperthyroidism, and hypothyroidism. The latter two states were induced by treatment with L-thyroxine and methimazole, respectively. The X-ray equatorial reflections were recorded at a time resolution of 10 ms to study the mass movement of myosin cross-bridges from thick to thin filaments. The myosin isomer content was measured by gel electrophoresis which showed that V3 isomer was predominant in euthyroid muscle and 27% of myosin was V1 isomer in hyperthyroid muscle. The intracellular free Ca concentration was measured by using the aequorin method. The peak Ca concentration was similar in all three states, but in the hypothyroid state the time-to-peak was longer and the decay was slower. The time-to-peak of twitch tension was shorter in hyperthyroidism and longer in hypothyroidism than in euthyroidism. The different time courses of twitch tension in different thyroid states accompanied a cross-bridge movement which closely followed the tension development. In hyperthyroidism, the cross-bridge movement significantly preceded tension development, suggesting that hyperthyroid myosin (V1) has a longer latency period between the shift to the vicinity of the thin filament and force development.
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PMID:Cross-bridge and calcium behavior in ferret papillary muscle in different thyroid states. 1149 56


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