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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calponin is an actin-associated protein that appears to play an auxiliary regulatory role in the contraction of smooth muscle. We report here on the mechanisms for regulation of calponin phosphorylation in the endothelin-1-induced contraction of porcine coronary artery. Treatment of strips of porcine artery with endothelin-1 increased calponin phosphorylation and contraction in a concentration-dependent manner. The time course of the phosphorylation was biphasic, with the response to endothelin-1. The extent of phosphorylation reached a maximum within 5 min of stimulation with 10(-7)M endothelin-1 and then it declined rapidly to reach a minimum at 20 min. A potent inhibitor of protein kinase C, GF109203X, inhibited both calponin phosphorylation and contraction that were induced by endothelin-1 at 5 min, without an inhibition for myosin light chain phosphorylation. Protein phosphatase inhibitor, okadaic acid, had no effect on the extent of phosphorylation at 5 min, but it significantly inhibited the subsequent decrease in calponin phosphorylation. In contrast, in PDBu-treated strips of coronary artery, okadaic acid caused a significant steady increase of the extent of calponin phosphorylation. Our results suggest that calponin phosphorylation might be regulated by protein kinase C and okadaic acid sensitive protein phosphatases, in the endothelin-1-induced contraction of porcine coronary artery.
J Mol Cell Cardiol 1999 Jun
PMID:Regulatory mechanisms of calponin phosphorylation in endothelin-1-induced contraction of porcine coronary artery. 1037 2

Cardiac contraction is triggered by the cyclic interaction of the "molecular motor" protein myosin with the actin filament, consuming ATP as the energy source to produce tension or shortening. The myosin heavy chain (MHC) contains the actin- and ATP-binding sites and represents the molecular motor of muscle contraction. This review describes the various subunits of human heart myosin in health and disease and discusses their functions. Two different MHC genes (alpha and beta) with distinct biochemical features are expressed in the human heart. Alpha-MHC confers a higher ATPase activity and higher shortening velocity to the heart than beta-MHC. Motor function is regulated by myosin light chain (MLC) isoforms. Expression of the atrial MLC-1 isoform in the hypertrophied human ventricle increases cross-bridge cycling and contractility. It is suggested that MLC-1 acts as a MHC/actin tether. Weakening of this tether increases myosin function. MLC-2 slows the rate of tension development of myosin. This relative inhibition is relieved upon phosphorylation of the MLC-2 perhaps caused by "swing-out" of cross-bridges from the myosin filament. Mutations in all ventricular myosin subunits have been found in patients with hypertrophic cardiomyopathy.
J Mol Med (Berl) 1999 Jul
PMID:Tuning the human heart molecular motors by myosin light chains. 1049

The adult rodent heart adapts to increased work load by reexpression of its fetal genes, for example, beta-myosin heavy chain (MHC), in order to improve contractile function. However, the human ventricle regulates contractility by expression of atrial essential myosin light chain (ALC-1) rather than beta-MHC. We evaluated the impact of both mechanisms in patients with hypertrophic cardiomyopathy. MHC isoform expression was quantified at the mRNA and protein levels by reverse transcriptase polymerase chain reaction and immunoblotting, respectively. Although alpha-MHC mRNA was detected in control and hypertrophied human ventricular tissue, alpha-MHC protein was not observed. Similarly, we investigated the expression of ALC-1 by two-dimensional polyacrylamide gel electrophoresis and the clinical and hemodynamic parameters of the patients with hypertrophic cardiomyopathy. We found a significant positive correlation between ALC-1 protein expression and dP/dtmax in the hypertrophied human ventricle in vivo. Correlations between dP/dtmax and expression of protein for the ryanodine receptor and L-type Ca2+ channel were excluded. Our data suggest that reexpression of ALC-1 improves the contractile state of the adult human heart. We propose that two evolutionarily divergent compensatory mechanisms for increased work demand exist in the mammalian heart: MHC regulation in rodents and essential MLC regulation, of cardiac contractility, in humans.
J Mol Med (Berl) 1999 Sep
PMID:Expression of atrial myosin light chains but not alpha-myosin heavy chains is correlated in vivo with increased ventricular function in patients with hypertrophic obstructive cardiomyopathy. 1056

Ca(2+)-regulated motility is essential to numerous cellular functions, including muscle contraction. Systems with troponin C, myosin light chain, or calmodulin as the Ca(2+) receptor have evolved in striated muscle and other types of cells to transduce the cytoplasm Ca(2+) signals into allosteric conformational changes of contractile proteins. While these Ca(2+) receptors are homologous proteins, their coupling to the responding elements is quite different in various cell types. The Ca(2+) regulatory system in vertebrate striated muscle represents a highly specialized such signal transduction pathway consisting of the troponin complex and tropomyosin associated with the actin filament. To understand the molecular mechanism in the Ca(2+) regulation of muscle contraction and cell motility, we have revealed a preserved ancestral close linkage between the genes encoding two of the troponin subunits, troponin I and troponin T, in the genome of mouse. The data suggest that the troponin I and troponin T genes may have originated from a single locus and evolved in parallel to encode a striated muscle-specific adapter to couple the Ca(2+) receptor, troponin C, to the actin-myosin contractile machinery. This hypothesis views the three troponin subunits as two structure-function domains: the Ca(2+) receptor and the signal transducing adapter. This model may help to further our understanding of the Ca(2+) regulation of muscle contraction and the structure-function relationship of other potential adapter proteins which are converged to constitute the Ca(2+) signal transduction pathways governing nonmuscle cell motility.
J Mol Evol 1999 Dec
PMID:Preserved close linkage between the genes encoding troponin I and troponin T, reflecting an evolution of adapter proteins coupling the Ca(2+) signaling of contractility. 1059 79

In this study we describe the identification and structure-function analysis of a novel death-associated protein (DAP) kinase-related protein, DRP-1. DRP-1 is a 42-kDa Ca(2+)/calmodulin (CaM)-regulated serine threonine kinase which shows high degree of homology to DAP kinase. The region of homology spans the catalytic domain and the CaM-regulatory region, whereas the remaining C-terminal part of the protein differs completely from DAP kinase and displays no homology to any known protein. The catalytic domain is also homologous to the recently identified ZIP kinase and to a lesser extent to the catalytic domains of DRAK1 and -2. Thus, DAP kinase DRP-1, ZIP kinase, and DRAK1/2 together form a novel subfamily of serine/threonine kinases. DRP-1 is localized to the cytoplasm, as shown by immunostaining and cellular fractionation assays. It binds to CaM, undergoes autophosphorylation, and phosphorylates an exogenous substrate, the myosin light chain, in a Ca(2+)/CaM-dependent manner. The truncated protein, deleted of the CaM-regulatory domain, was converted into a constitutively active kinase. Ectopically expressed DRP-1 induced apoptosis in various types of cells. Cell killing by DRP-1 was dependent on two features: the status of the catalytic activity, and the presence of the C-terminal 40 amino acids shown to be required for self-dimerization of the kinase. Interestingly, further deletion of the CaM-regulatory region could override the indispensable role of the C-terminal tail in apoptosis and generated a "superkiller" mutant. A dominant negative fragment of DAP kinase encompassing the death domain was found to block apoptosis induced by DRP-1. Conversely, a catalytically inactive mutant of DRP-1, which functioned in a dominant negative manner, was significantly less effective in blocking cell death induced by DAP kinase. Possible functional connections between DAP kinase and DRP-1 are discussed.
Mol Cell Biol 2000 Feb
PMID:Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis. 1062 61

The purpose of this study was to examine whether the nitric oxide donor S-nitrosoglutathione (GSNO) relaxes canine tracheal smooth muscle (CTSM) strips by decreasing Ca(2+) sensitivity [i.e., the amount of force for a given intracellular Ca(2+) concentration ([Ca(2+)](i))]. We further investigated whether GSNO decreases Ca(2+) sensitivity by altering the relationship between regulatory myosin light chain (rMLC) phosphorylation and [Ca(2+)](i) and the relationship between force and rMLC phosphorylation. GSNO (100 microM) relaxed intact CTSM strips contracted with 45 mM KCl by decreasing Ca(2+) sensitivity in comparison to control strips without significantly decreasing [Ca(2+)](i). GSNO reduced the amount of rMLC phosphorylation for a given [Ca(2+)](i) but did not affect the relationship between isometric force and rMLC phosphorylation. These results show that in CTSM strips contracted with KCl, GSNO decreases Ca(2+) sensitivity by affecting the level of rMLC phosphorylation for a given [Ca(2+)](i), suggesting that myosin light chain kinase is inhibited or that smooth muscle protein phosphatases are activated by GSNO.
Am J Physiol Lung Cell Mol Physiol 2000 Mar
PMID:S-nitrosoglutathione-induced decrease in calcium sensitivity of airway smooth muscle. 1071 May 24

The Rab/Ypt small G proteins are essential for intracellular vesicle trafficking in mammals and yeast. The vesicle-docking process requires that Ypt proteins are located in the vesicle membrane. C-terminal geranylgeranyl anchors mediate the membrane attachment of these proteins. The Rab escort protein (REP) is essential for the recognition of Rab/Ypt small G proteins by geranylgeranyltransferase II (GGTase II) and for their delivery to acceptor membranes. What effect an alteration in the levels of prenylated Rab/Ypt proteins has on vesicle transport or other cellular processes is so far unknown. Here, we report the characterization of a yeast REP mutant, mrs6-2, in which reduced prenylation of Ypt proteins occurs even at the permissive temperature. A shift to the restrictive temperature does not alter exponential growth during the first 3 h. The amount of Sec4p, but not Ypt1p, bound to vesicle membranes is reduced 2.5 h after the shift compared with wild-type or mrs6-2 cells incubated at 25 degrees C. In addition, vesicles fail to be polarized towards the bud and small budded binucleate cells accumulate at this time point. Growth in 1 M sorbitol or overexpression of MLC1, encoding a myosin light chain able to bind the unconventional type V myosin Myo2, or of genes involved in cell wall maintenance, such as SLG1, GFA1 and LRE1, suppresses mrs6-2 thermosensitivity. Our data suggest that, at least at high temperature, a critical minimal level of Ypt protein prenylation is required for maintaining vesicle polarization.
Mol Microbiol 2000 Mar
PMID:Low levels of Ypt protein prenylation cause vesicle polarization defects and thermosensitive growth that can be suppressed by genes involved in cell wall maintenance. 1076 Jan 32

Embryonic stem cells will cluster and differentiate into embryoid bodies, which can develop spontaneous rhythmic contractions. From these embryoid bodies, cardiomyocytes can be isolated based on density by a discontinuous Percoll gradient. These cardiomyocytes differentiate into ventricular myocytes, which is demonstrated by the expression of the ventricular specific isoform of the myosin light chain 2 gene. In this study the functional expression of ion channels was compared between fetal cardiomyocytes (in vivo) and stem cell derived cardiomyocytes (in vitro). Sodium and calcium currents together with transient potassium currents could be detected in early developmental stages (<day 14) both in vivo and in vitro. In the early stages, we found a limited number of cells expressing I(Kr)and virtual absence of I(Ks). The characteristics and distribution of currents are similar in both cell types. The current characteristics were identical for ventricular compared to atrial or undifferentiated stem cell derived cardiomyocytes, despite differences in expression of regulatory myosin light chain proteins. The myocyte differentiation was verified in a limited number of cardiomyocytes following the patch clamp procedure by immunocytochemistry.
J Mol Cell Cardiol 2000 May
PMID:Differentiation of cardiomyocytes in floating embryoid bodies is comparable to fetal cardiomyocytes. 1077 88

We tested the hypothesis that increases in force at a given cytosolic Ca(2+) concentration (i.e., Ca(2+) sensitization) produced by muscarinic stimulation of canine tracheal smooth muscle (CTSM) are produced in part by mechanisms independent of changes in regulatory myosin light chain (rMLC) phosphorylation. This was accomplished by comparing the relationship between rMLC phosphorylation and force in alpha-toxin-permeabilized CTSM in the absence and presence of acetylcholine (ACh). Forces were normalized to the contraction induced by 10 microM Ca(2+) in each strip, and rMLC phosphorylation is expressed as a percentage of total rMLC. ACh (100 microM) plus GTP (1 microM) significantly shifted the Ca(2+)-force relationship curve to the left (EC(50): 0.39 +/- 0.06 to 0.078 +/- 0.006 microM Ca(2+)) and significantly increased the maximum force (104.4 +/- 4.8 to 120.2 +/- 2.8%; n = 6 observations). The Ca(2+)-rMLC phosphorylation relationship curve was also shifted to the left (EC(50): 1.26 +/- 0.57 to 0.13 +/- 0.04 microM Ca(2+)) and upward (maximum rMLC phosphorylation: 70.9 +/- 7.9 to 88.5 +/- 5. 1%; n = 6 observations). The relationships between rMLC phosphorylation and force constructed from mean values at corresponding Ca(2+) concentrations were not different in the presence and absence of ACh. We find no evidence that muscarinic stimulation increases Ca(2+) sensitivity in CTSM by mechanisms other than increases in rMLC phosphorylation.
Am J Physiol Lung Cell Mol Physiol 2000 Jul
PMID:Relationship between force and regulatory myosin light chain phosphorylation in airway smooth muscle. 1089 2

In this study, we examined the molecular mechanism of myosin-bound protein phosphatase (MBP) regulation by insulin and evaluated the role of MBP in insulin-mediated vasorelaxation. Insulin rapidly stimulated MBP in confluent primary vascular smooth muscle cell (VSMC) cultures. In contrast, VSMCs isolated from diabetic and hypertensive rats exhibited impaired MBP activation by insulin. Insulin-mediated MBP activation was accompanied by a rapid time-dependent reduction in the phosphorylation state of the myosin-bound regulatory subunit (MBS) of MBP. The decrease observed in MBS phosphorylation was due to insulin-induced inhibition of Rho kinase activity. Insulin also prevented a thrombin-mediated increase in Rho kinase activation and abolished the thrombin-induced increase in MBS phosphorylation and MBP inactivation. These data are consistent with the notion that insulin inactivates Rho kinase and decreases MBS phosphorylation to activate MBP in VSMCs. Furthermore, treatment with synthetic inhibitors of phosphatidylinositol-3 kinase (PI3-kinase), nitric oxide synthase (NOS), and cyclic guanosine monophosphate (cGMP) all blocked insulin's effect on MBP activation. We conclude that insulin stimulates MBP via its regulatory subunit, MBS partly by inactivating Rho kinase and stimulating NO/cGMP signaling via PI3-kinase as part of a complex signaling network that controls 20-kDa myosin light chain (MLC20) phosphorylation and VSMC contraction.
Mol Endocrinol 2000 Sep
PMID:Regulation of myosin-bound protein phosphatase by insulin in vascular smooth muscle cells: evaluation of the role of Rho kinase and phosphatidylinositol-3-kinase-dependent signaling pathways. 1097 15


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