Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tibialis anterior (TA) muscles of 6-month-old and 24-month-old male Wistar rats, after being characterized, at the fast motor unit level, for twitch properties, were dissected and processed by a procedure [Margreth A., Damiani E., Tobaldin G. Biochem Biophys Res Commun 1993; 197: 1303-1311] aimed at obtaining a representative total membrane fraction comprising 70-80% of the total muscle content of sarcoplasmic reticulum (SR) and transverse tubule (TT) membranes (about 20 mg protein/g). Skeletal muscle membranes were analyzed for protein composition, and the content and functional properties of specific components of the free and junctional subcompartments of the SR and of junctional TT. Our results, while confirming a twitch prolongation in TA of old rats, do not demonstrate any associated age-related change concerning: (a) the overall number and functional properties of Ca2+ pumps, as characterized by kinetic parameters, Ca(2+)-dependency, and the protein isoform specificity of SR Ca(2+)-ATPase; (b) the number of functional junctional SR Ca(2+)-release channels, on the basis of Bmax values for high-affinity binding of [3H]-ryanodine to skeletal muscle membranes at optimal Ca2+; (c) the overall muscle dihydropyridine receptor/ryanodine receptor (RyR) ratio. We conclude from these findings, and the additional negative evidence for changes in membrane density of specific components of junctional SR, including 60 kDa Ca(2+)-calmodulin protein kinase, that this membrane domain, like the Ca(2+)-pump domain of the SR, are in no way basically altered at early stages of the aging process, as investigated here. Because of that, we allege particular significance to the occurrence of age-related, specific abnormalities in regulation of RyR in rat TA. The main supportive evidence is as follows: (a) an increased sensitivity to Ca2+ of the RyR of old muscle, and, more importantly; (b) an increased sensitivity to caffeine of [3H]ryanodine binding to the RyR at optimal Ca2+ and also optimal for the activity of the Ca(2+)-release channel. The results reported here also demonstrate that there are two classes of caffeine sites in rat TA muscle, as defined by differences in EC50 values at resting (pCa 7) and at high Ca2+ (pCa 4-5), that sites involved in stimulation of [3H]-ryanodine binding to the RyR are distinguished by a higher affinity (caffeine below mM), and that only these sites undergo age-related changes. Thus, although the underlying age-related abnormality of the RyR remains to be elucidated, it appears to satisfy the requirement for being regarded as a specific change, which in itself might argue for its being fundamentally related to the twitch prolongation of the muscle.
...
PMID:Age-related abnormalities in regulation of the ryanodine receptor in rat fast-twitch muscle. 865 53

Of two neurosecretory PC12 cell clones that respond to NO donors and 8-bromo-cGMP with similar increases in cADP-ribose and that possess molecularly similar Ca2+ stores, only one (clone 16A) expresses the type 2 ryanodine receptor, whereas the other (clone 27) is devoid of ryanodine receptors. In PC12-16A cells, activation of the NO/cGMP pathway induced slow [Ca2+]i responses, sustained by release from Ca2+ stores. In contrast, PC12-27 cells were insensitive to NO donors. Likewise, in PC12-16A cells preincubated with NO donors, Ca2+ stores were partially depleted, as revealed by a test with thapsigargin, whereas those in clone 27 were unchanged. The NO-induced Ca2+ release was increased synergistically by caffeine, and the corresponding store depletion was magnified by ryanodine. The specificity for the NO/cGMP pathway was confirmed by the effects of two blockers of cGMP-dependent protein kinase I, while the role of cADP-ribose was demonstrated by the effects of its antagonist, 8-amino-cADP-ribose, administered to permeabilized cells. These results demonstrate in neurosecretory cells a ryanodine receptor activation pathway similar to that known in sea urchin oocytes. The signaling events described here could be of great physiological importance, especially in the nervous system.
...
PMID:The type 2 ryanodine receptor of neurosecretory PC12 cells is activated by cyclic ADP-ribose. Role of the nitric oxide/cGMP pathway. 866 43

This paper demonstrates and characterizes the inhibition of ryanodine binding caused by the phosphorylation of the 160/150-kDa proteins in skeletal muscle sarcoplasmic reticulum (SR). Inhibition of ryanodine binding was obtained by preincubation of SR membranes with ATP + NaF . The inhibition was characterized by the following findings: (a) If ATP was replaced by AdoPP[NH]P, inhibition of ryanodine binding activity was not observed. (b) The inhibitory effect of preincubation with ATP + NaF, like the phosphorylation of 150/160-kDa proteins, was Ca2+ dependent. (c) Inhibition of ryanodine binding, as the protein phosphorylation, was not observed if NaF (> 30 mM) was replaced with okadaic acid. (d) The optimal pH for the inhibition and the phosphorylation was about 7.0. (e) Both the phosphorylation of the 160/150-kDa proteins and inhibition of ryanodine binding were prevented by dichlorobenzimidazole riboside and hemin, inhibitors of casein kinase II. (f) Dephosphorylation of the 160/150-kDa proteins prevented the inhibition of ryanodine binding. (g) The presence of NP-40 during the phosphorylation prevented both the 160/150-kDa phosphorylation and the inhibition of ryanodine binding. Furthermore, a linear relationship was obtained between the degree of ryanodine binding inhibition and the level of phosphorylation of the 160/150-kDa proteins, as controlled by ATP or NaF concentrations. The binding affinity for Ca2+ of the ryanodine receptor (RyR) was modified by phosphorylation of the 160/150-kDa proteins, decreasing by up to 100-fold. The phosphorylation of the SR membranes resulted in an elimination of ryanodine binding sites with slight effect on the ryanodine binding affinity. These results suggest the modulation of the properties of the RyR by phosphorylation/dephosphorylation of the 160/150-kDa proteins. The identification of the phosphorylated 160/150-kDa proteins, their kinase, and the structural interactions between them and the RyR are presented in the accompanying paper.
...
PMID:Modulation of the skeletal muscle ryanodine receptor by endogenous phosphorylation of 160/150-kDa proteins of the sarcoplasmic reticulum. 876 98

In this study we investigated the sarcoplasmic reticulum (SR), alongside myofibrillar phenotype, in muscle samples from five Myotonic Dystrophy (DM) patients and five control individuals. DM muscles exhibited as a common feature, a decrease in the slow isoform of myosin heavy chain (MHC) and of troponin C in myofibrils. We observed a match between myofibrillar changes and changes in SR membrane markers specific to fiber type, i.e. the fast (SERCA1) Ca(2+)-ATPase isoform increased concomitantly with a decrease of protein phospholamban (PLB), which in native SR membranes colocalizes with the slow (SERCA2a) SR Ca(2+)-ATPase, and regulates its activity depending on phosphorylation by protein kinases. Our results outline a cellular process selectively affecting slow-twitch fibers, and non-degenerative in nature, since neither the total number of Ca(2+)-pumps or of ryanodine receptor/Ca(2+)-release channels, or their ratio to the dihydropyridine receptor/voltage sensor in junctional transverse tubules, were found to be significantly changed in DM muscle. The only documented, apparently specific molecular changes associated with this process in the SR of DM muscle, are the defective expression of the slow/cardiac isoform of Ca(2+)-binding protein calsequestrin, together with an increased phosphorylation activity of membrane-bound 60 kDa Ca(2+)-calmodulin (CaM) dependent protein kinase. Enhanced phosphorylation of PLB by membrane-bound Ca(2+)-CaM protein kinase also appeared to be most pronounced in biopsy from a patient with a very high CTG expansion, as was the overall 'slow-to-fast' transformation of the same muscle biopsy. Animal studies showed that endogenous Ca(2+)-CaM protein kinase exerts a dual activatory role on SERCA2a SR Ca(2+)-ATPase, i.e. either by direct phosphorylation of the Ca(2+)-ATPase protein, or mediated by phosphorylation of PLB. Our results seem to be consistent with a maturational-related abnormality and/or with altered modulatory mechanisms of SR Ca(2+)-transport in DM slow-twitch muscle fibers.
...
PMID:Skeletal muscle sarcoplasmic reticulum phenotype in myotonic dystrophy. 884 17

1. Raising the intracellular [Ca2+] for 10 s at 23 degrees C abolished depolarization-induced force responses in mechanically skinned muscle fibres of toad and rat (half-maximal effect at 10 and 23 microM, respectively), without affecting the ability of caffeine or low [Mg2+] to open the ryanodine receptor (RyR)/Ca2+ release channels. Thus, excitation-contraction coupling was lost, even though the Ca2+ release channels were still functional. Coupling could not be restored in the duration of an experiment (up to 1 h). 2. The Ca(2+)-dependent uncoupling had a Q10 > 3.5, and was three times slower at pH 5.8 than at pH 7.1. Sr2+ caused similar uncoupling at twenty times higher concentration, but Mg2+, even at 10 mM, was ineffective. Uncoupling was not noticeably affected by removal of ATP or application of protein kinase or phosphatase inhibitors. 3. Confocal laser scanning microscopy showed that the transverse tubular system was sealed in its entirety in mechanically skinned fibres and that its integrity was maintained in uncoupled fibres. Electron microscopy revealed distorted or severed triad junctions and Z-line aberrations in uncoupled fibres. 4. Only when uncoupling was induced at a relatively slow rate (e.g. over 60 s with 2.5 microM Ca2+) could it be prevented by the protease inhibitor leupeptin (1 mM). Immunostaining of Western blots showed no evidence of proteolysis of the RyR, the alpha 1-subunit of dihydropyridine receptor (DHPR) or triadin in uncoupled fibres. 5. Fibres which, whilst intact, were stimulated repeatedly by potassium depolarization with simultaneous application of 30 mM caffeine showed reduced responsiveness after skinning to depolarization but not to caffeine. Rapid release of endogenous Ca2+, or raised [Ca2+] under conditions which minimized the loss of endogenous diffusible myoplasmic molecules from the skinned fibre, caused complete uncoupling. Taken together, these results suggest that Ca(2+)-dependent uncoupling can also occur in intact fibres. 6. This Ca(2+)-dependent loss of depolarization-induced Ca2+ release may play an important feedback role in muscle by stopping Ca2+ release in localized areas where it is excessive and may be responsible for long-lasting muscle fatigue after severe exercise, as well as contributing to muscle weakness in various dystrophies.
...
PMID:Raised intracellular [Ca2+] abolishes excitation-contraction coupling in skeletal muscle fibres of rat and toad. 884 31

Certain eukaryotic cells can sense changes in their extracellular Ca2+ concentration through molecular structures termed Ca(2+)-sensing receptors (CaRs). We have shown recently that in the bone-resorbing osteoclast, a unique cell surface-expressed ryanodine receptor (RyR), functions as the CaR. The present study demonstrates that the sensitivity of this receptor is modulated by physiological femtomolar concentrations of the bone-conserving hormone, calcitonin. Calcitonin was found to inhibit cytosolic Ca2+ responses to both Ca2+ and Ni2+. The latter inhibition was mimicked by amylin (10(-12) M), calcitonin gene-related peptide (10(-12) M), cholera toxin (5 micrograms/l) and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) (2.5 x 10(-4) or 5 x 10(-4) M) and was reversed by the protein kinase A phosphorylation inhibitor, IP-20. Finally, using a quench flow module, we showed that cellular cAMP levels rise to a peak within 25 ms of calcitonin application; this is consistent with the peptide's rapid effect on CaR activation. We conclude, therefore, that cAMP plays a critical role in the control of CaR function by calcitonin.
...
PMID:Regulation of extracellular calcium sensing in rat osteoclasts by femtomolar calcitonin concentrations. 885 26

The mechanisms required for cGMP-induced Ca2+ release in the sea urchin egg were investigated using both egg homogenates and intact eggs. The postulated pathway of cGMP-dependent protein kinase (PKG) activation of ADP-ribosyl cyclase for production of cADPR to activate the ryanodine receptor Ca2+ channel was tested with a variety of activators (cGMP analogs and cIMP) and inhibitors (Rp-8-pCPT-cGMPS, 3-aminopyridine NAD, nicotinamide, and spermine). Our observations are consistent with Ca2+ release by cGMP in the egg being dependent on an isoform of PKG that is distinct from the mammalian enzyme. PKG activity in the sea urchin egg was activated by cIMP, but was insensitive to cGMP analogs, which are potent activators of mammalian isoenzymes. Surprisingly, it appears the activation of the cGMP-dependent Ca2+ release pathway was unnecessary during fertilization. Inhibitors of either PKG or ADP-ribosyl cyclase activities did not prevent the transient rise in intracellular Ca2+ activity in heparin-loaded eggs during fertilization. These results suggest the synthesis of cADPR during fertilization is not necessary for regulating the Ca2+ event.
...
PMID:The cyclic GMP-mediated calcium release pathway in sea urchin eggs is not required for the rise in calcium during fertilization. 894 94

In the adult myocardium the Ca2+ uptake and release functions of the sarcoplasmic reticulum (SR) are known to be regulated by a membrane-associated Ca2+-calmodulin-dependent protein kinase (CaM kinase) which phosphorylates the Ca2+-pumping ATPase (Ca2+ pump), Ca2+ release channel (ryanodine receptor) and the Ca2+ pump-regulatory protein, phospholamban. The role of CaM kinase during development, however, has not been examined previously. The present study investigated the ontogenetic expression of SR-associated CaM kinase in the rabbit myocardium as well as development-related changes in CaM kinase-mediated phosphorylation of the SR proteins (Ca2+ pump, Ca2+ release channel and phospholamban) involved in transmembrane Ca2+ cycling. For these experiments, cardiac muscle homogenate and SR-enriched membrane fraction derived from fetal (21- and 28-days gestation), newborn (2 days postnatal) and adult New Zealand White rabbits were used. Western immunoblotting analysis detected the presence of phospholamban, Ca2+ pump and Ca2+ release channel in homogenate and SR at all ages tested. The amount of these proteins in the SR increased substantially during fetal and postnatal development. Phosphorylation studies revealed the presence of CaM kinase-dependent phosphorylation of the Ca2+ pump, Ca2+ release channel and phospholamban as early as 21-days gestation. This phosphorylation could be elicited with the addition of only Ca2+ and calmodulin indicating the presence of a SR-associated CaM kinase as early as 21-days gestation. This was confirmed using a delta-CaM kinase II-specific antibody. Phosphorylation per unit amount of each substrate was greater in the fetus and newborn compared to adult. Phosphorylation of phospholamban could be elicited by exogenous cAMP-dependent protein kinase (PKA) at all developmental stages studied. Activation of SR CaM kinase with Ca2+ and calmodulin, or induction of phospholamban phosphorylation by exogenous PKA, resulted in stimulation of the Ca2+ uptake activity of SR in fetal, newborn and adult heart. These results demonstrate early ontogenetic expression of the Ca2+ cycling proteins and CaM kinase in the SR and the concurrent development of phosphorylation-dependent regulation of SR Ca2+ cycling.
...
PMID:Ontogeny of sarcoplasmic reticulum protein phosphorylation by Ca2+--calmodulin-dependent protein kinase. 904 54

Signal transduction in gastric and intestinal smooth muscle is mediated by receptors coupled via distinct G proteins to various effector enzymes, including PI-specific PLC-beta 1 and PLC-beta 3, and phosphatidylcholine (PC)-specific PLC, PLD and PLA2. Activation of these enzymes is different in circular and longitudinal muscle cells, generating Ca(2+)-mobilizing (IP3, AA, cADPR) and other (DAG) messengers responsible for the initial and sustained phases of contraction, respectively. IP3-dependent Ca2+ release occurs only in circular muscle. Ca2+ mobilization in longitudinal muscle involves a cascade initiated by agonist-induced transient activation of PLA2 and formation of AA, AA-dependent depolarization of the plasma membrane and opening of voltage-sensitive Ca2+ channels. The influx of Ca2+ induces Ca2+ release by activating sarcoplasmic ryanodine receptor/Ca2+ channel and stimulates cADPR formation which enhances Ca(2+)-induced Ca2+ release. The initial [Ca2+]i transient in both muscle cell types results in Ca2+/calmodulin-dependent activation of MLC kinase, phosphorylation of MLC20 and interaction of actin and myosin. The sustained phase is mediated by a Ca(2+)-independent isoform of PKC, PKC-epsilon DAG for this process is generated by PLC- and PLD-mediated hydrolysis of PC. Relaxation is mediated by cAMP-and/or cGMP-dependent protein kinase which inhibit the initial [Ca2+]i transient and reduce the sensitivity of MLC kinase to [Ca2+]i. Relaxation induced by the main neurotransmitters, VIP and PACAP, involves two cascades, one of which reflects activation of adenylyl cyclase. A distinct cascade involves G-protein-dependent stimulation of Ca2+ influx leading to Ca2+/calmodulin-dependent activation of a constitutive eNOS in muscle cells; the generation of NO activates soluble guanylyl cyclase. The resultant activation of PKA and PKG is jointly responsible for muscle relaxation.
...
PMID:Signal transduction in gastrointestinal smooth muscle. 921 27

We have devised a novel procedure, employing Chaps rather than Triton [Costello B., Chadwick C., Saito A., Chu A., Maurer A., Fleischer S. J Cell Biol 1986; 103: 741-753], for obtaining vesiculated derivatives of the junctional face membrane (JFM) domain of isolated terminal cisternae (TC) from fast skeletal muscle of the rabbit. Enriched JFM is minimally contaminated with junctional transverse tubules. The characteristic ultrastructural features and the most essential features of TC function relating to this membrane domain-i.e. both the Ca(2+)-release system and the Ca2+ and calmodulin (CaM)-dependent protein kinase (CaM I PK) system-appear to be retained in enriched JFM. We show that our isolation procedure, yielding up to a 2.5-fold enrichment in ryanodine receptor (RyR) protein and in the maximum number of high affinity [3H]-ryanodine binding sites, does not alter the assembly for integral proteins associated with the receptor in its native membrane environment, i.e. FKBP-12, triadin and the structurally related protein junction [Jones L.R., Zhang L., Sanborn K., Jorgensen A., Kelley J. J Biol Chem 1995; 270: 30787-30796] having, in common, the property to bind calsequestrin (CS) in overlays in the presence of EGTA. The substrate specificity of endogenous CaM I PK is also the same as that of parent TC vesicles. Phosphorylation of mainly triadin and of a high M(r) polypeptide, and not of the RyR, is the most remarkable common property. Retention of peripheral proteins, like CS and histidine-rich Ca(2+)-binding protein, although not that endogenous CaM, and of a unique set of CaM-binding proteins, unlike that of junctional SR-specific integral proteins, is shown to be influenced by the concentration of Ca2+ during incubation of TC vesicles with Chaps. Characterization of RyR functional behaviour with [3H]-ryanodine has indicated extensive similarities between the enriched JFM and parent TC vessicles, as far as the characteristic bell shaped Ca(2+)-dependence of [3H]-ryanodine binding and the dose-dependent sensitization to Ca2+ by caffeine, reflecting the inherent properties of SR Ca(2+)-release channel, as well as concerning the stimulation of [3H]-ryanodine binding by increasing concentrations of KCl. Stabilizing the RyR in a maximally active state by optimizing concentrations of KCl (1 M), at also optimal concentrations of Ca2+ (pCa 4), rendered the receptor less sensitive to inhibition by 1 microM CaM, to a greater extent in the case of enriched JFM. That was not accounted for by any significant difference in the IC50 concentrations of CaM varying between 40 nM to approximately 80 nM, at low-intermediate and at high KCl concentrations, respectively. Additional results with enriched JFM using doxorubicin, a pharmacological Ca2+ channel allosteric modifier, strengthen the hypothesis that the conformational state at which RyR is stabilized, according to the experimental assay conditions for [3H]-ryanodine binding, directly influences CaM-sensitivity.
...
PMID:Functional behaviour of the ryanodine receptor/Ca(2+)-release channel in vesiculated derivatives of the junctional membrane of terminal cisternae of rabbit fast muscle sarcoplasmic reticulum. 929 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---