Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium fluxes across the sarcoplasmic reticulum membrane are regulated by phosphorylation of a 27,000-dalton membrane-bound protein termed phospholamban. Phospholamban is phosphorylated by three different protein kinases (cAMP-dependent, Ca2+.CAM-dependent and Ca2+.phospholipid dependent) at apparently distinct sites. Phosphorylation by each of the protein kinases increases the rates of active calcium transport by sarcoplasmic reticulum vesicles. The stimulatory effects of protein kinases on the calcium pump may be reversed by an endogenous protein phosphatase activity. The phosphoprotein phosphatase can dephosphorylate both the cAMP-dependent and the Ca2+.CAM-dependent sites of phospholamban. Phosphorylation of phospholamban also occurs in situ, in perfused beating hearts, during the peak of the inotropic response to beta-adrenergic stimulation. Reversal of the stimulatory effects is associated with dephosphorylation of phospholamban. Thus, in vivo and in vitro studies suggest that phospholamban is a regulator for the calcium pump in cardiac sarcoplasmic reticulum. The degree of phospholamban phosphorylation determined by the interaction of specific protein kinases and phosphatases may represent an important control for sarcoplasmic reticulum function and, thus, for the contraction-relaxation cycle in the myocardium. In this review, we summarize recent evidence on physical and structural properties of phospholamban, the proposed structural molecular models for this protein, and the significance of its regulatory role both in vitro and in situ.
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PMID:Regulation of cardiac sarcoplasmic reticulum function by phospholamban. 285 62

The effects of replacement of each of the individual Met in calmodulin (CaM) with Leu on the activation of two CaM target enzymes [smooth muscle myosin light chain kinase (smMLCK) and calcineurin (CN)] were investigated. The KD and Pmax (percentage maximal activation) values for activation of both enzymes by M76L-CaM were indistinguishable from wild-type (wt)-CaM, which is consistent with the location of Met-76 in the central linker that is not involved in target protein interaction. The other eight Met in CaM are exposed in the hydrophobic surfaces that are involved in target-enzymes binding, and in general equivalent effects are observed for substitutions of Leu for Met residues in homologous positions in the two CaM domains. However, the importance of the interaction of specific Met residues with the target enzyme depends on the particular enzyme. Leu substitution at Met-36 or Met-109 reduced the affinity of MLCK for the mutant and the maximal activation of CN. MLCK had a higher KD for M51L-CaM whereas M124L-CaM activated the kinase to only 68% of maximal activity induced by wt-CaM; these mutants were indistinguishable from wt-CaM in activation of CN. M71L- and M144L-CaMs behaved like wt-CaM in activation of MLCK, but activated the phosphatase to only about 80% of maximal activity induced by wt-CAM. M72L-CaM exhibited an increased affinity for MLCK compared to wt-CaM and slightly decreased maximal activation, whereas M145L-CaM exhibited maximal activation significantly greater than that due to wt-CaM; these mutants behaved like wt-CaM with respect to CN activation. Finally, a mutant CaM in which all four C-terminal Met were replaced by Leu (M4-CT-L4-CaM) had similar affinities for MLCK and CN as wt-CaM but maximal activation of these enzymes by this mutant was only 60-70% of that achieved with wt-CaM. These results imply that, in addition to removing the autoinhibitory domain from the active site of the target enzyme, CaM must induce a conformational change in the active site itself.
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PMID:Activation of calcineurin and smooth muscle myosin light chain kinase by Met-to-Leu mutants of calmodulin. 951 73

Two monoclonal antibodies (mAbs) raised against bovine calmodulin (CaM), CAM1 and CAM4, enable one to monitor conformational changes that occur in the molecule. The interaction of CAM1 with CaM depends on the Ca2+ occupancy of its Ca(2+)-binding sites. CAM4, in contrast, interacts with CaM in a Ca(2+)-independent manner, interacting with both holoCaM and EGTA-treated CaM to a similar extent. Their interaction with various CaMs, CaM tryptic fragments and chemically modified CaM, as well as molecular graphics, led to identification of the CAM1 and CAM4 epitopes on the C- and N-terminal lobes of CAM respectively. The two mAbs were used as macromolecular probes to detect conformational changes occurring in the CaM molecule upon binding of metal ions and target proteins and peptides. MAb CAM1 successfully detected changes associated with Al3+ binding even in the presence of Ca2+, indicating that Al3+ and Ca2+ ions may bind to the protein simultaneously, leading to a new conformation of the molecule. MAbs CAM1 and CAM4 were used to follow the interactions of CaM with its target peptides and proteins. Complexes with melittin, mastoparan, calcineurin and phosphodiesterase showed different immunological properties on an immuno-enzyme electrode, indicating unique structural properties for each complex.
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PMID:Interactions of calmodulin with metal ions and with its target proteins revealed by conformation-sensitive monoclonal antibodies. 1007 99

The results of the investigation of immunosuppressive activity of cyclolinopeptide A (CLA--cyclic hydrophobic nonapeptide present in the linseeds) and its analogs are discussed. The results obtained for other natural cyclic peptides showing structural similarities with CLA (antamanide, cycloamanides, hymenistatin, hymenamides) are also reviewed. It results from these investigations that the molecular mechanism of the CLA action is the same as that of cyclosporin A and FK-506 compound, i.e. it consists in formation of the complex with cyclophilin and inhibition--in this form--of the phosphatase activity of calcineurin. The results also suggest that the immunosuppressive activity of these compounds resides in their--Pro-Xxx-Phe- fragment, where Xxx is a hydrophobic (e.g. Leu, Val) or aromatic amino acid residue.
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PMID:Cyclolinopeptides and their analogs--a new family of peptide immunosuppressants affecting the calcineurin system. 1047 Apr 41

Nicotinic acetylcholine receptors (nAChRs) mediate fast excitatory neurotransmission in neurons and muscles. To identify nAChR accessory proteins, which may regulate their expression or function, we performed tandem affinity purification of the levamisole-sensitive nAChR from Caenorhabditis elegans, mass spectrometry of associated components, and RNAi-based screening for effects on in vivo nicotine sensitivity. Among the proteins identified was the calcineurin A subunit TAX-6, which appeared to function as a negative regulator of nAChR activity. We also identified five proteins not previously linked to nAChR function, whose inactivation conferred nicotine resistance, implicating them as positive regulators of nAChR activity. Of these, the copine NRA-1 colocalized with the levamisole receptor at neuronal and muscle plasma membranes, and, when mutated, caused reduced synaptic nAChR expression. Loss of SOC-1, which acts in receptor tyrosine kinase (RTK) signaling, also reduced synaptic levamisole receptor levels, as did mutations in the fibroblast growth factor receptor EGL-15, and another RTK, CAM-1. Thus, tandem affinity purification is a viable approach to identify novel proteins regulating neurotransmitter receptor activity or expression in model systems like C. elegans.
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PMID:Identification and characterization of novel nicotinic receptor-associated proteins in Caenorhabditis elegans. 1599 Aug 70

The ubiquitous Na+/H+ exchanger NHE1 is regulated by protein phosphorylation events, but the mechanisms involved are incompletely understood. We recently cloned NHE1 from the red blood cells of the winter flounder, Pleuronectes americanus (paNHE1), and demonstrated its activation by osmotic cell shrinkage, beta-adrenergic stimuli, and the Ser/Thr protein phosphatase PP1 and PP2A inhibitor calyculin A(CLA) (Pedersen et al. [2003] Am. J. Physiol. 284, C1561-C1576). Here, we investigate the mechanisms involved in paNHE1 activation by these stimuli. Osmotic shrinkage and CLA were only partially additive in their effects on paNHE1 activity, and CLA-mediated paNHE1 activation was inhibited by osmotic cell swelling. Activation by the beta-adrenergic agonist isoproterenol (IP) was fully additive to activation by osmotic shrinkage or CLA. IP-mediated, but neither shrinkage- nor CLA-mediated paNHE1 activation were associated with an increase in cellular cyclic adenosine monophosphate (cAMP) level. IP-mediated activation was partially blocked by the protein kinase A (PKA) inhibitor H89 (10 microM), whereas shrinkage- and CLA-mediated activation were unaffected. All three stimuli activated paNHE1 in a manner unaffected by inhibitors of protein kinase C (calphostin C, 5 microM) and protein kinase G (KT5823, 10 microM) as well as of myosin light chain kinase (ML-7, 10 microM). IP-mediated, but not shrinkage-mediated, paNHE1 activation was associated with an increase in serine phosphorylation of the paNHE1 protein. It is suggested that paNHE1 activation by osmotic shrinkage and by PP1/PP2A inhibition involves partially convergent signaling pathways, whereas activation of paNHE1 by beta-adrenergic stimuli is mediated by a separate pathway.
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PMID:Regulation of the Pleuronectes americanus Na+/H+ exchanger by osmotic shrinkage, beta-adrenergic stimuli, and inhibition of Ser/Thr protein phosphatases. 1667 60

We report three pediatric heart transplant (HTx) patients whose respiratory symptoms were successfully controlled with long-term, low-dose macrolide administration (clarithromycin: CAM; approximately 2.5 mg/kg bid). The first case was an 18-year-old boy who underwent HTx at the age of three for dilated cardiomyopathy (DCM). Beginning at age 5, he had repeated fevers and respiratory symptoms. He was diagnosed with chronic sinusitis at age 11 and sinobronchial syndrome with mild bronchiectasis at age 14. Administration of long-term, low-dose CAM and otolaryngeal topical therapy led to significant improvement of his symptoms. The second case was a 7-year-old boy who underwent HTx for DCM at age one. Starting at age 4, he had repeated fevers and cough due to atelectasis and pneumonia. As antibiotics and respiratory physical therapy proved ineffective, he received long-term, low-dose CAM, resulting in successful control of his atelectasis and recurrent pneumonia. The third case was a 13-year-old boy who underwent HTx at age 6 for DCM. He had chronic sinusitis starting at age 7, and was diagnosed with obstructive sleep apnea syndrome at age 10. Adenotonsillectomy and continuous positive airway pressure support therapy were indicated. At age 13, long-term, lowdose CAM administration was started following mycoplasma infection. In all three cases, the levels of calcineurin inhibitors (cyclosporine and tacrolimus) and everolimus were kept in the optimal range with careful drug monitoring. Longterm, low-dose macrolide administration effectively prevents and treats respiratory complications in pediatric HTx patients as long as attention is paid to potential drug interactions.
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PMID:The successful management of respiratory complications with long-term, low-dose macrolide administration in pediatric heart transplant recipients. 2529 1