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PubMed1991

Melatonin modifies calmodulin cell levels in MDCK and N1E-115 cell lines and inhibits phosphodiesterase activity in vitro.

The interaction between melatonin and calmodulin was explored. Calmodulin cell levels in MDCK and N1E-115 cells cultured with 10(-9) M melatonin were increased after 3 days but decreased after 6 days. Melatonin inhibited calmodulin-dependent phosphodiesterase and when either melatonin or [3H]melatonin was preincubated with calmodulin and separated by electrophoresis, comigration of calmodulin with the radioactivity as well as modification of the Ca2+ calmodulin shift were observed. The results point out that one of the mechanisms of action of melatonin is a calmodulin-melatonin interaction.

Animals↗
PubMed1992

Calmodulin transcription is limited to the nervous system during Drosophila embryogenesis.

We have examined the RNA expression pattern for the Drosophila calmodulin gene during embryogenesis by in situ hybridization to transcripts in whole embryos. Our results indicate that maternally derived calmodulin mRNA is homogeneously distributed throughout the early embryo, but that these maternal transcripts are lost by maximal germ band extension. Zygotic transcription of the gene in mid- to late-stage embryos is restricted to neural cell precursors and their progeny in both the central and peripheral nervous systems. Thus, activation of calmodulin transcription during embryonic development appears to mark a commitment to a neural fate. Northern blot analysis revealed that the two transcripts from the calmodulin gene are differentially expressed during embryogenesis. Comparison of Northern blot and in situ hybridization data indicates that the longer calmodulin mRNA is a nervous tissue-specific transcript. This suggests that neural-specific regulation of polyadenylation site usage occurs. We have also examined calmodulin expression in embryos homozygous for mutations in four loci which are known to affect nervous system development: numb, the achaete-scute complex, daughterless, and mastermind. The calmodulin transcription pattern is altered in embryos mutant for each of these loci, suggesting that regulation by these genes, either directly or indirectly, is taking place.

Animals↗
PubMed1988

Different developmental functions for calmodulin in Dictyostelium: trifluoperazine and R24571 both inhibit cell and pronuclear fusion but enhance gamete formation.

The calmodulin antagonists trifluoperazine and compound R24571 were used to study the function of calmodulin during sexual development in Dictyostelium discoideum. Calmodulin activity is required for both cell fusion and pronuclear fusion. However, cell fusion and pronuclear fusion were each maximally inhibited at different concentrations of the same inhibitor suggesting differential calmodulin activity during these events. In contrast, trifluoperazine and R24571 were both found to enhance rather than inhibit the formation of gametes. This suggests an additional role for calmodulin as a negative regulator of gamete development. These results provide evidence of a role for calmodulin as both a positive (biomembrane fusion) and a negative (gamete development) regulator of developmental events in Dictyostelium. They also reveal calmodulin as a mediator of pronuclear fusion for zygote development in this eukaryote.

Calmodulin↗
PubMed1988

Covalent conjugation of mammalian calmodulin with ubiquitin.

In this paper it is shown that mammalian calmodulin from bovine testis is a substrate for reticulocyte ubiquitin conjugating activity (UCA) forming a 1:1 covalent conjugate between bovine calmodulin and ubiquitin (uCaM). There is an absolute requirement for Ca2+ in the range of approximately 10 microM for ubiquitination of calmodulin to occur. This novel conjugate (uCaM) shows a Ca2+-dependent mobility change in polyacrylamide gel electrophoresis in the presence of SDS, indicating that the calmodulin-ubiquitin conjugate still retains the mobility change of native calmodulin. This conjugation reaction could be of prime importance for the intracellular turnover of calmodulin in the mammalian cell, although it cannot be excluded that the ubiquitin-calmodulin conjugate might in itself be of biological relevance.

Adenosine Triphosphate↗
PubMed1990

Calmodulin is a potent target for new hypothalamic neuropeptides.

Recently, five glycopeptides with coronaro-constrictory properties were isolated from bovine hypothalamus [(1988) Neurochemistry (USSR) 7, 519-524]. Calmodulin has been recognized in our laboratory as a target protein for the neuropeptides isolated from hypothalamus. The results of indirect enzyme-linked immunosorbent assay have shown that the new hypothalamic neuropeptides antagonize with the monospecific anti-calmodulin antibody for calmodulin binding although they are not fragments of calmodulin. The inhibitory potency of the peptides is dependent on their concentration and the length of the polypeptide chain. Four out of five peptides are effective in nM concentration range. Ca2+ stimulates the binding of peptides to calmodulin; however, immunocomplex can be formed in the absence of Ca2+ as well. The effects of trifluoperazine and peptides on the calmodulin/antibody interaction are not additive, suggesting the cooperativity between the binding sites on calmodulin. Under physiological conditions the presence of the peptides could produce distinct conformers of calmodulin which may exhibit altered potency for stimulation/inhibition of target enzymes.

Animals↗
PubMed1986

Structure of rat calmodulin processed genes with implications for a mRNA-mediated process of insertion.

Two distinct processed calmodulin genes of rat (lambda SC8 and lambda SC9) were identified, cloned and their DNA sequences determined. The existence of direct repeats of 19 base-pairs for lambda SC8 or 9 base-pairs for lambda SC9 at both ends of the coding plus non-coding regions suggested a possible involvement of a mRNA-mediated process of insertion. Total genomic Southern hybridization suggested the existence of at least three different calmodulin-related genes in the rat genome. The other gene was the bona fide calmodulin gene (lambda SC4) which was split into at least five exons. lambda SC9 contained insertions of one nucleotide and two 17 base-pair direct repeats in the coding region. These insertions cause frameshift mutations probably preventing it from encoding a functional calmodulin. It also carried an insertion of a rat middle repetitive sequence, identifier sequence (IDS: Sutcliffe et al., 1982) in the 3'-non-coding region. Otherwise, it consisted of an almost identical DNA sequence to that of the bona fide calmodulin gene (lambda SC4), including the 3'-non-coding region down to the poly(A) recognition signal, A-A-T-A-A-A. On the other hand, lambda SC8 did not possess frameshift mutations in the coding region, and hence was capable of encoding a functional protein. In fact, a probe specific to the lambda SC8 sequence identified a band in Northern blotting whose size was 300 nucleotides smaller than that of authentic calmodulin mRNA. Comparison of the nucleotide sequences showed that only the coding regions of these two processed genes were homologous, indicating that the divergence of these two processed genes from the common ancestor calmodulin was an ancient event.

Amino Acid Sequence↗
PubMed1987

Structure and sequence of the Drosophila melanogaster calmodulin gene.

A series of phage clones overlapping the single calmodulin gene locus of Drosophila melanogaster has been isolated and the exons of the gene positioned and sequenced within these clones. A calmodulin cDNA clone of the electric eel was used to identify these clones and to position the two major protein-coding exons of the gene. cDNA clones for D. melanogaster calmodulin were then isolated, characterized and used to identify the remaining exons. The gene consists of four exons separated by three introns of 3400 to 4300 bases in length. Exon 1 consists of the 5' untranslated region and the initiator ATG; exon 2 encodes amino acid residues 1 to 58.3; exon 3 encodes residues 58.3 to 139.3; and exon 4 encodes residues 139.3 to 148 and the 3' untranslated region. From the sequence of the 3' untranslated region and the lengths of the cDNA clones, two or three polyadenylation sites are indicated. Sequences potentially involved in the control of transcription of the gene and splicing of the mRNA product have been identified. Comparison of the intron-exon structures of the D. melanogaster calmodulin gene, the chick calmodulin gene, and other genes of the troponin C superfamily reinforces previous hypotheses that these genes arose from a common progenitor and permits identification of four introns that were probably present in the progenitor gene structure. The D. melanogaster calmodulin gene contains three of these introns, and the chick gene contains all four. These gene comparisons also indicate that the region of these genes encoding Ca2+-binding loop 3 is highly variable in structure. The chick and D. melanogaster calmodulin genes differ in this region, the chick gene containing a fifth intron here that is absent from the D. melanogaster gene.

Animals↗
PubMed1984

The presence and binding characteristics of calmodulin in microsomal preparations enriched in sarcoplasmic reticulum from rabbit skeletal muscle.

ATP-dependent oxalate facilitated calcium transport in sarcoplasmic reticulum (SR) preparations obtained from rabbit vastus lateralis muscle (fast skeletal muscle; Fsr) and soleus (slow skeletal muscle; Ssr) was determined. Addition of exogenous calmodulin did not stimulate calcium transport in either Fsr or Ssr preparations. Fsr and Ssr previously washed in 1 mM EGTA demonstrated a reduced capacity to transport Ca2+; the exogenous addition of calmodulin (0.24 microM) under these conditions, did not restore uptake activity but significantly decreased the steady-state level of Ca2+ uptake. Extracts of skeletal SR prepared by treatment with 0.2 mM EDTA and boiling produced significantly more stimulation of red cell Ca2+ATPase activity than extracts prepared by boiling alone. This stimulation of red cell Ca2+-ATPase was inhibited to a significant extent by 48/80, a known anti-calmodulin agent. Radioimmunoassay revealed that extracts prepared by boiling or EDTA-treatment followed by boiling contained considerable amounts of calmodulin. Washing with 1 mM EGTA, though, did not release any calmodulin from SR. These studies reveal that calmodulin is present in both Fsr and Ssr and can only be removed by harsh treatments. The role of calmodulin in skeletal muscle Ca2+-transport remains to be determined.

Animals↗
PubMed1984

Relation between Ca2+-ATPase and endogenous calmodulin of human erythrocyte membranes.

Short incubation of erythrocyte membranes with oleic acid releases Ca2+-independently bound endogenous calmodulin together with a minor fraction of membrane-associated proteins without destruction of the membranes. The released endogenous calmodulin is similar if not identical to cytosolic calmodulin reversibly bound to ghosts in a Ca2+-dependent manner. The release of endogenous calmodulin proceeds without affecting the activity of Ca2+-ATPase when ghosts are incubated with oleic acid in the presence of Ca2+ plus ATP and thereafter freed from oleic acid by washings with serum albumin. Kinetic parameters of Ca2+-ATPase of ghosts with and without endogenous calmodulin are identical as are amounts of exogenous calmodulin bound to these ghosts. Thus, endogenous calmodulin does not function as an essential part of Ca2+-ATPase.

Adenosine Triphosphate↗
PubMed1985

Elevation of calmodulin in avian muscular dystrophy.

In an attempt to understand the mechanism of calcium accumulation in myopathies, changes in the major calcium-binding protein, calmodulin, was studied in genetically dystrophic chickens. Measurements by radioimmunoassay revealed an increase in the calmodulin concentration of dystrophic chicken muscles. Poly A-containing RNA(s) of fast and slow muscles from the normal and dystrophic chicks were hybridized with [32P]-labeled calmodulin cDNA probe by the dot-hybridization technique. Densitometric scan of the autoradiogram showed that the calmodulin mRNA levels of dystrophic fast muscles (pectoralis and posterior latissimus dorsi) were approximately two-fold higher than those of the corresponding normal muscles. No significant change in calmodulin and calmodulin messenger RNA of slow muscle (ALD) was found in dystrophic chickens. Our results suggest that increased calcium flux within the dystrophic muscle may be modulated by calmodulin.

Animals↗
PubMed1993

Calmodulin expression during proliferative activation of human T lymphocytes.

We have investigated the levels of calmodulin mRNA species and calmodulin protein during proliferation of human T lymphocytes. Quiescent lymphocytes expressed the 1.7 kb transcript of CaM I, the 1.4 kb of CaM II and the 2.3 kb of CaM III. Phytohaemagglutinin added to peripheral blood lymphocytes induced DNA replication which started at 48 h and reached a maximum at 72 h after activation. All the species of calmodulin mRNAs, including the 4.0 kb transcript of CaM I and the 0.8 kb of CaM III which were not detected in quiescent cells, increased during lymphocyte proliferation. At 72 h after activation, the increase of CaM I and CaM II transcripts were found to be 2-fold whereas CaM III mRNAs increased 9-fold. The cellular content of calmodulin protein was also found to increase during proliferation and calmodulin accumulations in cytosol and nuclei of activated cells were observed. Two calmodulin binding proteins of 180 and 170 kD were found to increase in the nuclei of proliferating lymphocytes, whereas on the contrary 3 other calmodulin binding proteins of 110, 62 and 60 kD decreased during proliferation.

Antibodies, Monoclonal↗
PubMed1988

Developmental changes in protein phosphorylation in chicken forebrain. II. Calmodulin stimulated phosphorylation.

The development of calmodulin stimulated protein phosphorylation, with particular reference to calmodulin-stimulated protein kinase II (CMK II), was investigated in 3 subcellular fractions of chicken forebrain: cytosol (S3), crude synaptic plasma membranes (P2-M) and occluded cytosol (P2-S). Changes in the level of calmodulin-stimulated phosphorylation of endogenous proteins occurred over a protracted time course and were not complete until after day 52 post-hatching. By day 15 post-hatching, calmodulin-stimulated phosphoproteins characteristic of embryonic fractions had all disappeared and those characteristic of adult tissue were present but not necessarily at their mature levels. The levels of CMK II were estimated from the autophosphorylation of the alpha-subunit which was the only phosphoprotein present at 53,000 Da in the 3 fractions. Overall, calmodulin-stimulated phosphorylation and CMK II levels were low in embryonic brain and high in adult brain but two specific changes in CMK II were observed during development: (1) although CMK II concentrations increased in both membrane and cytosolic fractions until day 23 the kinase was predominantly cytoplasmic (approximately 75%) until day 23, after which it became increasingly membrane bound so that by day 52 post-hatching the majority of CMK II was present in the synaptic membrane fraction, and (2) the relative concentrations of the alpha- and beta-subunits changed from an alpha:beta-value of approximately 1:1 in the 19 day embryo to approximately 1:2 by 15 days post-hatch after which no further change was seen. The occurrence of major changes in the calmodulin stimulated protein phosphorylation system for up to 6-8 weeks after synapse formation is completed in the forebrain, provides further support for the existence of a synapse maturation phase of neuronal differentiation which is distinct from synapse formation. This phase involves only a specific subset of the developmental changes occurring in the calmodulin-stimulated phosphorylation system.

Aging↗
PubMed1994

Distribution and regulation of calmodulin mRNAs in rat brain.

Selective oligonucleotide probes were developed to determine the distribution and hormonal regulation of different calmodulin genes in rat brain and the relationship to calmodulin-dependent adenylate cyclase activity. (1) Probes directed against known CaMI, CaMII and CaMIII mRNA sequences selectively recognized molecular mRNA species of approximately 4.1 and 1.7 (CaMI mRNA), 1.4 (CaMII mRNA) and 2.0 and 1.0 kb (CaMIII mRNA) in rat brain. All three calmodulin genes appeared actively coexpressed at high levels in neuronal cell layers, as revealed by in situ hybridization and northern analysis. (2) Adrenalectomy selectively attenuated levels of CaMIII, but not CaMI or CaMII mRNA, in both cerebral cortex and hippocampus. (3) Adrenalectomy also decreased calmodulin dependent adenylate cyclase activity in hippocampal, but not cortical, cell membranes. (4) Corticosterone administration prevented adrenalectomy effects on hippocampal adenylate cyclase activity and calmodulin mRNA levels. However, steroid treatment also increased forskolin-stimulated enzyme activity in cerebral cortex, but not in hippocampus. These results suggest that hormonal factors regulate calmodulin gene expression in adult brain. Further evidence is required to establish the temporal interrelationships between steroid regulation of calmodulin and its target proteins.

Adenylyl Cyclases↗
PubMed1985

Calmodulin, synchronous and asynchronous release of neurotransmitter.

Evidence collected from studies on a wide range of secretory cells suggests that calmodulin may play an important role in stimulus-secretion coupling. Work on synaptosomes, central synaptic preparations and chromaffin cell preparations indicates that calmodulin probably also acts as the intracellular Ca2+-receptor for secretion in neuronal cells, Ca2+-binding resulting in activation of protein kinases and phosphorylation of certain secretory vesicle proteins. Studies on the effects of calmodulin-binding drugs at peripheral synapses have given surprising results, particularly the finding that evoked (synchronous) transmitter release is not suppressed by calmodulin inhibition, though asynchronous release can be markedly inhibited. It is suggested that the insensitivity of synchronous release to drug treatment is due to the fact that only vesicle-bound calmodulin is involved in this form of transmitter secretion. Asynchronous release, however, involves recruitment of cytosolic calmodulin and can therefore be inhibited by calmodulin-binding drugs.

Adrenal Medulla↗
PubMed1992

Regulation of Ca2+ uptake in skeletal muscle by 1,25-dihydroxyvitamin D3: role of phosphorylation and calmodulin.

Experiments were carried out to obtain information about the mechanism underlying the fast action of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in skeletal muscle. N-2'-o-dibutyryladenosine-3',5'-cyclic monophosphate (dbcAMP), similarly as 1,25(OH)2D3 (5 x 10(-10) M), rapidly increased 45Ca uptake by soleus muscle from vitamin D-deficient chicks (+25% and +98% at 3 min and 10 min, respectively) in a dose-dependent manner. The effects of the cAMP analog (10 microM) and 1,25(OH)2D3 could be abolished by the Ca(2+)-channel blocker nifedipine and the calmodulin antagonist flufenazine. Calmodulin binding by two muscle microsomal proteins of 28 kDa and 30 kDa was stimulated within 1 min of exposure of the tissue to 1,25(OH)2D3. Direct effects of the sterol on membrane calmodulin binding were shown with isolated microsomes. The 1,25(OH)2D3-mediated rise of [125I]calmodulin binding to microsomal membranes was dependent on the presence of medium ATP. Forskolin (10 microM) and cAMP (10 microM) also increased [125I]calmodulin binding (+75% and +64%, respectively, with respect to controls). Pretreatment of microsomal membranes with cAMP-dependent protein kinase inhibitor (1 microgram/ml) or addition of alkaline phosphates (1 U/ml) after hormonal treatment caused complete inhibition of 1,25(OH)2D3-induced [125I]calmodulin binding to microsomal membrane proteins. These results imply modifications of membrane protein phosphorylation through the cAMP signal pathway and in turn of calmodulin binding in the mechanism by which 1,25(OH)2D3 rapidly stimulates skeletal muscle Ca2+ uptake.

Adenosine Triphosphate↗
PubMed1996

Effect of insulin treatment on smooth muscle calmodulin levels in rats with long-term streptozotocin-diabetes.

Altered responses to several agonists have been reported in various smooth muscles from experimentally-diabetic animals suggesting a defective contractile process of smooth muscle. Recently, decreased smooth muscle calmodulin levels have been reported in streptozotocin-diabetic rats. However, the effectiveness of insulin on the decreased calmodulin levels in diabetic rats has not been questioned. Therefore, the present study was designed to examine the effect of insulin on smooth muscle calmodulin levels from streptozotocin-diabetic rats. Calmodulin levels of the smooth muscle were measured by a radioimmunoassay technique. Streptozotocin diabetes caused a significant decrease in tissue calmodulin levels of smooth muscles. Insulin therapy for 20 days did not correct the changes in calmodulin levels of rat smooth muscles, although it normalised blood glucose in streptozotocin-diabetic rats. These findings suggest that the altered smooth muscle calmodulin may contribute the defective contractile responses in diabetes and these changes may be resistant to insulin therapy.

Animals↗
PubMed1985

Interaction of calcium-binding proteins with calmodulin-dependent guanylate cyclase in Tetrahymena plasma membrane.

Addition of bovine brain calmodulin and S-100 inhibited Tetrahymena calmodulin-induced stimulation of guanylate cyclase, but they did not affect enzymatic activity in the presence of calcium alone. Troponin C shows little effect on the cyclase activity regardless of the presence or absence of Tetrahymena calmodulin. The inhibitory effects of brain calmodulin and S-100 were overcome by the addition of Tetrahymena calmodulin, but not by calcium. Both calmodulins from Tetrahymena and bovine brain elicited stimulation of heart phosphodiesterase, while troponin C and S-100 did not affect the phosphodiesterase activity in the presence and absence of Tetrahymena calmodulin.

Animals↗
PubMed1985

Microinjection of calmodulin antibodies into cultured chromaffin cells blocks catecholamine release in response to stimulation.

Polyclonal monospecific antibodies raised in sheep against rat testis calmodulin demonstrated cross-reactivity with bovine adrenal medullary chromaffin cell calmodulin. This antibody immunoprecipitated a [35S]methionine-labelled protein from chromaffin cell extracts prepared from [35S]methionine prelabelled cells that comigrated on a sodium dodecylsulfate gel electrophoresis system with calmodulin. In addition, an excess of non-radioactive exogenous calmodulin was shown to readily compete with this labelled endogenous protein for the antibodies' binding sites. Erythrocyte ghosts were used as vehicles for microinjecting either preimmune immunoglobulin G or anti-calmodulin immunoglobulin G into chromaffin cells following a polyethylene glycol-induced cell fusion procedure. The efficiency of ghost cell fusion was monitored and found to be 43.6 +/- 1% (n = 33). Cell morbidity subsequent to fusion and microinjection was negligible (87.8 +/- 0.6% of the total cell population were viable cells; n = 33) as determined by the Trypan Blue exclusion test. The delivery of intact antibodies raised against calmodulin directly into the cytoplasm of cultured chromaffin cells by erythrocyte ghost-mediated microinjection, inhibited catecholamine output in response to stimulation by either acetylcholine (10(-4) M) or a depolarizing concentration of potassium (56 mM). However, under these conditions, the chromaffin cell's ability to accumulate exogenous catecholamines through a high affinity uptake system, as well as the kinetic parameters that characterize this uptake mechanism remained unaltered. Furthermore, microinjection of preimmune immunoglobulin G did not modify either catecholamine uptake or stimulation-induced amine release from chromaffin cells. It therefore appears that calmodulin may play a role in the process of stimulus-secretion coupling in the chromaffin cell in culture while it is of little significance to the high affinity amine uptake mechanism.

Adrenal Medulla↗