Disease relevance of Myl1

• In iv mutants with situs inversus, the asymmetric expression of alpha-skeletal actin and MLC3F was inverted, showing that this process is regulated by global left-right axis cues, initiated before gastrulation [1].
• Furthermore, it may play a role in various cardiomyopathies where atrial MLC isoforms are partially expressed in ventricles or ventricular MLC isoforms are partially expressed in atria [2].
• Severe, chronic pulmonary arterial banding for 14 days resulted in right ventricular dilatation and dysfunction, associated with right atrial enlargement, and angiographic evidence of tricuspid regurgitation [3].
• Hypoxia stimulates atrial natriuretic peptide gene expression in cultured atrial cardiocytes [4].
• Activation of the gene for atrial natriuretic factor during in vitro cardiac myogenesis by P19 embryonal carcinoma cells [5].

High impact information on Myl1

• Two loci have been characterized in the mouse Mus musculus, which are homologous to the mRNAs encoding myosin light chains MLC1F and MLC3F, two proteins with a common -COOH terminal sequence [6].
• Genetic information specific for the N-terminal sequences is encoded in four exons, at 3.5 and 14.3 kb for MLC1F, and 3.8 and 4.5 kb for MLC3F, upstream of the first common exon [6].
• The pseudogene is not genetically linked to the functional MLC1F/MLC3F locus in the genome of Mus musculus [6].
• One of these loci is an intronless pseudogene, absent from the mouse species Mus spretus; alterations in its nucleotide sequence preclude it from generating a functional MLC1F or MLC3F [6].
• Homozygous mutants had no circulating or atrial ANP, and their blood pressures were elevated by 8 to 23 millimeters of mercury when they were fed standard (0.5 percent sodium chloride) and intermediate (2 percent sodium chloride) salt diets [7].

Chemical compound and disease context of Myl1

• Expression of extracellular ligand-binding domain of murine guanylate cyclase/atrial natriuretic factor receptor cDNA in Escherichia coli [8].
• Recent studies have suggested that inositol-1,4,5-trisphosphate-receptor (IP3R)-mediated Ca2+ release plays an important role in the modulation of excitation-contraction coupling (ECC) in atrial tissue and the generation of arrhythmias, specifically chronic atrial fibrillation (AF) [9].
• Mice made obese with gold thioglucose developed cardiac hypertrophy associated with increases in ANP in atrial tissue and plasma [10].
• Since a bovine brain ganglioside mixture (Cronassial) has been extensively studied for its effect on peripheral diabetic neuropathy, a group of diabetic mice was treated throughout the sixth month with this drug (10 mg/kg/day i.p.). The ganglioside treated animals showed a marked recovery of atrial function and cardiac NE concentration [11].

Biological context of Myl1

• Transcription at this locus is regulated by a 3' skeletal muscle enhancer element, which directs correct temporal and tissue-specific expression from the MLC1F promoter in transgenic mice [12].
• Our results show that these regulatory elements direct strong expression of lacZ in skeletal muscle; the transgene, however, is activated 4-5 d before the endogenous MLC3F promoter, at the time of initiation of MLC1F transcription [12].
• To investigate the role of this enhancer in regulation of the MLC3F promoter in vivo, we have analyzed reporter gene expression in transgenic mice containing lacZ under transcriptional control of the mouse MLC3F promoter and 3' enhancer element [12].
• Transcripts for the ventricular/slow (MLC1V) and another fast skeletal myosin light chain (MLC3F) are not detected in skeletal muscle before 15 d p.c., which marks the beginning of the fetal stage of muscle development [13].
• This demonstrates that these myosin light chain mRNAs accumulate with differing kinetics, and that MLC3F mRNA accumulation is nerve-dependent during fetal development [14].

Anatomical context of Myl1

• In situ hybridization, with 35S-labeled antisense cRNAs, demonstrates the versatility of primary myotubes in that transcripts for (1) alpha-cardiac and alpha-skeletal actin, (2) MHCembryonic, MHCperinatal and MHC beta/slow, and (3) MLC1A, MLC1F and MLC3F are detectable at 14 days gestation [15].
• In fetuses treated with beta-bungarotoxin and which therefore develop in the absence of functional nerve, MLC1A and MLC1F undergo normal transitions but MLC3F mRNA accumulation is significantly retarded [14].
• Subsequently, MLC3F transcripts are down-regulated in the left ventricle, and by E12.5 expression is restricted to both atria and left-ventricular trabeculae [16].
• When atrial volume was increased by changing atrial pressure, extracellular fluid (ECF) translocation and ANP secretion proportionately increased [17].
• A 3' enhancer can activate MLC1F and MLC3F promoters in differentiated muscle cells in vitro and in transgenic mice; both promoters, however, are activated at the time of MLC1F transcript accumulation [18].

Associations of Myl1 with chemical compounds

• The NH2-terminal region of MLC1A/MLC1emb, thought to be involved in the actomyosin interaction, shows conservation with MLC1V but not with MLC1F suggesting a shared functional domain in these cardiac isoforms [19].
• Effect of native and synthetic atrial natriuretic factor on cyclic GMP [20].
• Reduced plasma epinephrine and corticosterone levels and adrenal medullary EGR-1 protein levels in CRH knockout versus WT mice during stress indicate that the HPA axis plays a crucial role in regulation of the PNMT gene expression in these organs.Cardiac atrial PNMT gene expression with stress is also dependent on intact HPA axis [21].
• 3. Mean arterial pressure and atrial, LV and RV mass were greater in ANP-/- mice than in ANP+/+ mice fed the basal salt diet [22].
• We confirm this intracaveolar localization by stereoimaging colloidal gold-labeled antibody to the prohormone in electron micrographs of glutaraldehyde/osmium tetroxide-fixed positively stained atrial thin sections [23].

Physical interactions of Myl1

• The membrane-bound form of guanylate cyclase/atrial natriuretic factor receptor (GC/ANF-R) is a 135 kDa transmembrane glycoprotein which binds ANF with high affinity [8].

Regulatory relationships of Myl1

• Furthermore, during the course of ANF purification, the ANF-induced increase of cGMP production by kidney cells paralleled the heightened specific natriuretic activity of the atrial factor [20].
• However, GLUT4 but not vp165 is additionally localised in the regulated secretory pathway in atrial cardiomyocytes [24].
• Endothelin-1-induced arrhythmogenic Ca2+ signaling is abolished in atrial myocytes of inositol-1,4,5-trisphosphate(IP3)-receptor type 2-deficient mice [9].
• 1. Peak outward K+ current densities are attenuated significantly in atrial myocytes isolated from P15 and adult Kv2.1N216Flag-expressing animals and in P15 cells exposed to AsODNs targeted against either Kv1.5 or Kv2 [25].
• Phospholamban gene transcript levels are much lower in murine atria as compared to murine ventricles and this reduced phospholamban expression has been suggested to result in enhanced atrial contractile parameters [26].

Other interactions of Myl1

• In contrast, the cardiac MLC1A mRNA is initially more abundant than that encoding the skeletal MLC1F isoform [13].
• However, although left-sided identity is later maintained by Pitx2 genes, we found that Pitx2c null embryos have normal left-biased expression of alpha-skeletal actin and MLC3F [1].
• An additional 47 backcross progeny from a cross between C57BL/10ScSn and B10.L-Lshr/s mice were examined for the cosegregation of Myl-1 and Vil RFLPs with Lsh phenotypic differences [27].
• Changes in atrial volume and ECF translocation and ANP secretion were positively correlated [17].
• The rostrocaudal positional gradient of transgene expression documented for MLC1F transgenic mice (Donoghue, M., J. P. Merlie, N. Rosenthal, and J. R. Sanes. 1991. Proc. Natl. Acad. Sci. USA. 88:5847-5851) is not seen in MLC3F transgenic mice [12].

Analytical, diagnostic and therapeutic context of Myl1

• Ventricular region-restricted expression of the luciferase reporter in the embryonic heart, as assessed by immunofluorescence and direct assay of reporter activity in microdissected atrial and ventricular muscle specimens, was confirmed from at least day 15 pc on [28].
• MR imaging was performed on a Bruker 3T imaging magnet using a custom radiofrequency coil following contrast perfusion of the atrial and ventricular chambers [29].
• Using Tokuyasu's classic technique, we now show by immunoelectron microscopy of glutaraldehyde-fixed and cryosectioned mouse and rat atria that antibody against atrial natriuretic peptide prohormone is present within caveolae of in situ atrial myocytes [23].
• Plasma ANP concentrations in anesthetized mice and ANP content and secretion in isolated atrial preparations were determined by radioimmunoassay [30].
• METHODS: K(ATP) channel currents were recorded from isolated mouse atrial cells with patch-clamp techniques [30].

References