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)

The relationships among 153 EF-hand (calcium-modulated) proteins of known amino acid sequence were determined using the method of maximum parsimony. These proteins can be ordered into 12 distinct subfamilies--calmodulin, troponin C, essential light chain of myosin, regulatory light chain, sarcoplasmic calcium binding protein, calpain, aequorin, Stronglyocentrotus purpuratus ectodermal protein, calbindin 28 kd, parvalbumin, alpha-actinin, and S100/intestinal calcium-binding protein. Eight individual proteins--calcineurin B from Bos, troponin C from Astacus, calcium vector protein from Branchiostoma, caltractin from Chlamydomonas, cell-division-cycle 31 gene product from Saccharomyces, 10-kd calcium-binding protein from Tetrahymena, LPS1 eight-domain protein from Lytechinus, and calcium-binding protein from Streptomyces--are tentatively identified as unique; that is, each may be the sole representative of another subfamily. We present dendrograms showing the relationships among the subfamilies and uniques as well as dendrograms showing relationships within each subfamily. The EF-hand proteins have been characterized from a broad range of organismal sources, and they have an enormous range of function. This is reflected in the complexity of the dendrograms. At this time we urge caution in assigning a simple scheme of gene duplications to account for the evolution of the 600 EF-hand domains of known sequence.
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PMID:Evolution of EF-hand calcium-modulated proteins. I. Relationships based on amino acid sequences. 211 31

To characterize the relationship between force production and Ca2+ occupancy of troponin C, investigators have related peak intracellular Ca2+, measured with a variety of Ca2(+)-indicators, and peak force during twitches. Inherent in the force-[Ca2+] relationship is the responsiveness of the myofilaments to Ca2+ which can be altered by different pharmacological manipulations. In this study we compared the force-[Ca2+] relationship obtained in aequorin-injected papillary muscles and saponin skinned trabeculae from control, right ventricular pressure-overload hypertrophy (POH), and hyperthyroid ferret hearts. In POH, the twitch and [Ca2+]i transient were prolonged as compared to control. Force-[Ca2+] relationships from skinned fiber preparations were superimposable between control and POH. The peak force-peak [Ca2+]i relationship in intact muscles from POH was shifted to the left as compared to control. In hyperthyroid hearts, the twitch and [Ca2+]i were abbreviated. Force-[Ca2+]i relationships from skinned fiber preparations were superimposable between control and thyrotoxic hearts. The peak force-peak [Ca2+]i relationship in intact muscles from hyperthyroid hearts was shifted to the right as compared to control. Our findings indicate that time course changes in the calcium transient artifacturally shift the peak force-peak calcium relationship in a predictable manner. Therefore, this relationship can not be used to address changes at the level of the myofilaments as previously suggested.
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PMID:Intracellular calcium related to force development in twitch contraction of mammalian myocardium. 214 83

The effects of sympathomimetic amines on Ca2+ transients and isometric contractions were assessed in isolated rabbit papillary muscles in which multiple superficial cells had been microinjected with the calcium-sensitive bioluminescent protein aequorin. In the presence of beta-adrenoceptor blockade, the alpha-receptor agonist phenylephrine increased both the amplitude of the aequorin signals and the force of contraction in a concentration-dependent manner. However, the maximum increase in the aequorin signals was less than 10% of that produced by the beta-receptor agonist isoproterenol, while the maximum increase in force of contraction produced by alpha-stimulation was about 50% of that elicited via beta-adrenoceptors. For a given increase in the force of contraction, stimulation of alpha-adrenoceptors produced much less change in the amplitude of the aequorin signals than did elevation of the extracellular Ca2+ concentration; we interpret this to mean that the positive inotropic effect of alpha-adrenoceptor stimulation is in large part the result of an increase in myofibrillar sensitivity to Ca2+. Stimulation of alpha-adrenoceptors produced little change or a slight decrease in the duration of the aequorin signal and an increase in the duration of contraction, while stimulation of beta-adrenoceptors significantly decreased the time to peak and duration of both the aequorin signals and the contractions. For a given level of inotropic effect, high concentrations of isoproterenol often increased the aequorin signals more than did elevations of Ca2+, which is consistent with other evidence that the cyclic AMP-dependent phosphorylation of troponin I leads to a decrease in myofibrillar Ca2+ sensitivity. However, concentrations of isoproterenol that did not produce evidence of this sort of desensitization also abbreviated the contractions much more than they did the aequorin signals. This suggests that the traditionally accepted mechanisms--a decrease in the Ca2+ affinity of troponin C and an acceleration of Ca2+ uptake by the sarcoplasmic reticulum--may not be sufficient to account for the actions of beta-receptor stimulation on the time course of contraction. In the absence of blocking agents, the naturally occurring catecholamines norepinephrine, epinephrine, and dopamine appear to influence the function of the rabbit papillary muscle through both alpha- and beta-adrenoceptors. Dopamine has a relatively greater effect on alpha-adrenoceptors than the other catecholamines.
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PMID:Actions of sympathomimetic amines on the Ca2+ transients and contractions of rabbit myocardium: reciprocal changes in myofibrillar responsiveness to Ca2+ mediated through alpha- and beta-adrenoceptors. 282 9

The Ca(II)-dependent photoprotein aequorin produces the luminescence of the marine coelenterate Aequorea victoria. The complete amino acid sequence of aequorin has been determined. A complete set of nonoverlapping peptides was produced by cyanogen bromide cleavage. These peptides were aligned by using the amino-terminal sequence of the intact protein and the sequences of selected arginyl and lysyl cleavage products. Although the aequorin preparations employed in these studies were homogeneous by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the presence of a minimum of 3 isotypes was demonstrated by the location of 17 sites of sequence microheterogeneity. Two amino acid variants were observed at each of 16 positions while 1 position had 3 different replacements. The protein as isolated has 189 amino acids with an unblocked amino terminus. According to the sequence reported here, the molecular weight of the apoprotein is 21 459 while that of the holoprotein is 21 914. The molecule possesses three internally homologous domains which were judged to be EF-hand Ca(II) binding domains by several different criteria. Aequorin is homologous to troponin C and to calmodulin. These findings demonstrate that aequorin is a member of the Ca(II) binding protein superfamily.
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PMID:Amino acid sequence of the calcium-dependent photoprotein aequorin. 286 97

1. The signal transduction process mediated by cyclic AMP that leads to the characteristic positive inotropic effect (PIE) in association with a positive lusitropic effect (acceleration of rate of twitch relaxation) has been well established. Relationships between accumulation of cyclic AMP, changes in intracellular Ca2+ transients and the PIE differ, however, depending on the mechanism of particular drugs that affect different steps in the metabolism of cyclic AMP. Selective partial agonists of beta 1-adrenoceptors and inhibitors of phosphodiesterase (PDE) III cause the accumulation of less cyclic AMP for a given PIE than does isoproterenol. In addition, in aequorin-microinjected canine ventricular muscle, selective inhibitors of PDE III, OPC 18790 and Org 9731, produced smaller decreases in the responsiveness of myofilaments to Ca2+ ions than isoproterenol, while a partial agonist of beta 1-adrenoceptors, denopamine, elicits a decrease in Ca2+ responsiveness of the same extent as does isoproterenol. 2. Activation of myocardial alpha 1-adrenoceptors, as well as stimulation of receptors for endothelin and angiotensin II, which accelerates hydrolysis of phosphoinositide (PI) to result in production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) are associated with very similar inotropic regulation: (1) the dependence on the species of animals of induction of the PIE; (2) an excellent correlation between the extent of acceleration of hydrolysis of PI and the PIE; (3) isometric contraction curves associated with a negative lusitropic effect; (4) the PIE associated with increases in myofibrillar responsiveness to Ca2+ ions; and (5) the selective inhibition of the PIE by an activator of protein kinase C (PKC), phorbol 12,13-dibutyrate (PDBu), with little effect on the PIE of isoproterenol and Bay k 8644. 3. A novel class of cardiotonic agents, namely, Ca2+ sensitizers such as EMD 53998 and Org 30029, act on the Ca(2+)-binding site of troponin C, increasing the affinity of these sites for Ca2+ ions, or at the actin-myosin interface to facilitate the cycling of cross-bridges. These agents produce a PIE with little change or decrease in Ca2+ transients and may bring about a significant breakthrough in the development of drugs for reversal of myocardial failure in the treatment of congestive heart failure.
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PMID:The effects of various drugs on the myocardial inotropic response. 771 48

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

Effects of the Ca2+ sensitizer N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride (Org-30029) on the myocardial contractile depression induced by acidosis and 2,3-butanedione monoxime (BDM) were investigated in aequorin-loaded canine ventricular myocardium. The peak Ca2+ transient-peak force relation during administration of Org-30029 (10(-4) to 10(-3) M) was shifted to the left and upward compared with the relation for elevation of the extracellular Ca2+ concentration ([Ca2+]o) (2.5-12.5 mM). Acidosis (pH 6.6) depressed the force with a small increase in the peak Ca2+ transient. BDM (3 mM) depressed the force with no change in the peak and duration of the Ca2+ transient, indicating that BDM may inhibit selectively the cross-bridge interaction. During acidosis or in the presence of BDM, elevation of [Ca2+]o increased the peak Ca2+ transient to the same extent as that in the control, but the force was inhibited. In contrast, Org-30029 increased the force to a level equivalent to the control with a slight change in the peak Ca2+ transient. In addition, during acidosis, Org-30029 (10(-3) M) increased the force in association with a slight decrease in the peak Ca2+ transient. Thus Org-30029 can reverse the myocardial contractile depression induced by a decrease in the Ca2+ sensitivity of myofilaments, as occurs in pathophysiological situations such as acidosis in cardiac ischemia. Org-30029 may exert the Ca(2+)-sensitizing effect by an increase in the affinity of troponin C for Ca2+ and by a direct action on the cross-bridge interaction.
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PMID:Ca2+ sensitizer Org-30029 reverses acidosis- and BDM-induced contractile depression in canine myocardium. 894 98

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

We investigated the contribution of sarcoplasmic reticulum (SR) and Na+/Ca2+ exchanger in the tension-dependent change in the decay of the Ca2+ transients (CaT) in euthyroid (Eu) and hyperthyroid (Hy) myocardium. Hy was induced by thyroxine treatment to enhance the rate of SR Ca2+ uptake. With the use of the aequorin method, CaT and tension in twitch contraction were simultaneously measured under various conditions (changing muscle length and Ca2+ concentration in solution). In both groups, the decay time of CaT (DT) showed a significant dependence on the developed tension, but the tension dependence of DT in Hy was significantly less than in Eu. In the presence of caffeine (3 mM), the tension dependence of DT in Hy became apparent as in Eu. Inhibition of Na+/Ca2+ exchanger by replacing Na+ with Li+ did not affect the dependence in Hy. The normalized extra Ca2+, which is the Ca2+ concentration change in response to a quick length change, in Hy was similar to that in Eu. pCa-tension relations of skinned trabeculae measured at different lengths (1.9 and 2.3 micrometer) were nearly identical in both groups. These results indicate that the tension-dependent change in the affinity of troponin C for Ca2+ works in both Eu and Hy myocardium and that the tension-dependent change in DT is influenced by the Ca2+ uptake rate of SR.
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PMID:Modulation of Ca2+ transient decay by tension and Ca2+ removal in hyperthyroid myocardium. 988 43

The mechanisms of the slower time courses of Ca2+ transients (CaT) and contraction in diabetic (diabetes mellitus, DM) myocardium were studied. The aequorin method was applied to papillary muscles of streptozotocin-induced DM and control rats. The time courses of CaT and tension of twitch in DM were slower than those in control, although the magnitudes of the CaT and contraction were identical. The dependence of CaT decay time and relaxation time on developed tension in DM and control rats differed. The length-tension relation in twitch and the pCa-tension relation in tetanus were identical in the two groups. The magnitude of extra Ca2+ (transient increase in intracellular Ca2+ concentration induced by a quick release in tetanus) was identical in both groups. pCa-tension relations of skinned trabeculae at different sarcomere lengths were nearly identical. The cross-bridge cycling rate (CCR) in DM was slower than that in control. These results indicate that the tension-dependent change in the Ca2+ affinity of troponin C in DM myocardium functions as in control myocardium. The slower time courses of CaT and tension in DM myocardium are caused by slower Ca2+ uptake by the sarcoplasmic reticulum and the slower CCR.
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PMID:Alterations in contractile properties and Ca2+ handling in streptozotocin-induced diabetic rat myocardium. 1060 Aug 36


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