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PubMed1987

Calcium effects on calmodulin lysine reactivities.

The differential reactivities of individual lysines on porcine testicular calmodulin were determined by trace labeling with high specific activity [3H]acetic anhydride as a function of the molar ratio of Ca2+ to calmodulin. In progressing from the Ca2+-depleted form of the protein to a Ca2+:calmodulin molar ratio of 5:1, six of the seven lysyl residues exhibited a modest 1.5- to 3.0-fold increase in reactivity. Lys 75, in contrast, was enhanced in reactivity greater than 20-fold. When the change in reactivity of each lysine was normalized as a percentage of the maximum change, most of the residues were found to fall into two distinct classes. One class, comprising lysines 94 and 148 from the two carboxy terminal Ca2+-binding domains 3 and 4, respectively, exhibited about 90% of their reactivity change when the Ca2+:calmodulin molar ratio was 2:1, and these residues were perturbed very little upon further addition of Ca2+. The other class, encompassing lysines 13, 21, and 30 from the amino terminal domain 1 and Lys 75 from the extended helix connecting the two globular lobes of calmodulin, underwent most of their overall reactivity change (55-70%) between 2 and 5 equivalents of Ca2+ per mol of calmodulin. Lys 77 was distinct in its pattern of change, undergoing approximately equal changes with each Ca2+ increment. These results are consistent with a model where Ca2+ first binds to the two carboxy terminal sites of calmodulin with no apparent preference, concomitant with minor alterations in the microenvironments of lysines in the unoccupied amino terminal domains. The third and fourth Ca2+ ions then bind to these latter two domains, again with no evidence of preference, with little change in the lysine reactivities at the carboxy terminus of the molecule. The environments of groups in the central helix appear to undergo changes in a manner that reflects their proximity to the amino and carboxy terminal domains. In the course of this work, it was found that Lys 94 in apocalmodulin is specifically perturbed by the addition of EGTA, suggesting that the chelating agent may interact with calmodulin at or near the third Ca2+-binding domain.

Acetic Anhydrides↗

PubMed1989

Interaction of amiodarone and its analogs with calmodulin.

Benzofurans have important actions on the electrical properties of myocardium; the biochemical basis of those actions is not known. Crystallographic examination of these compounds has revealed that benzofurans share structural homologies with the traditional calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene and trifluoperazine. In the present study, the ability of amiodarone, desethylamiodarone, and benziodarone to displace the fluorescent ligand 8-anilino-1-naphthalene sulfonic acid (ANS) from calmodulin, to modulate the fluorescence emission of dansylcalmodulin, and to inhibit the activation by calmodulin of bovine brain cyclic nucleotide phosphodiesterase and human erythrocyte membrane Ca2+-ATPase were investigated at concentrations ranging from 10(-8) to 10(-6) M. These benzofurans displaced ANS from calmodulin with nearly equal efficiency upon forming a 1:1 complex with that protein. Each of these compounds also produced a decreased fluorescence emission of dansylcalmodulin, but with relative efficiencies being desethylamiodarone greater than amiodarone greater than benziodarone. Amiodarone and desethylamiodarone inhibited calmodulin-stimulable phosphodiesterase activity with similar potencies. Amiodarone and benziodarone inhibited calmodulin-stimulable Ca2+-ATPase activity equally, but desethylamiodarone had no effect. The observed differential effects of the amiodarone analogs suggest that calmodulin may possess multiple benzofuran-binding sites that are recognized by specific targets and ligands of this Ca2+-binding protein and that the cellular action of amiodarone and its analogs may reflect calmodulin antagonism.

Amiodarone↗

PubMed1990

Potent peptide inhibitors of smooth muscle myosin light chain kinase: mapping of the pseudosubstrate and calmodulin binding domains.

Smooth muscle myosin light chain kinase (MLCK) is activated by calcium-calmodulin and, in turn, phosphorylates and activates the smooth muscle actomyosin ATPase, resulting in muscle contraction. The amino acid sequence of the regulatory domain of MLCK is known, and it contains a region that binds calmodulin and also bears a strong homology to the phosphorylation site in the substrate. Thus, it has been called the "pseudosubstrate". It has been proposed that calmodulin activates MLCK by binding to and reversing the autoinhibitory function of the pseudosubstrate. Synthetic peptides based on this sequence inhibit MLCK both by binding to calmodulin and by competing with the substrate at the active site. In the work reported here, we have synthesized a large number of peptides from the regulatory region of MLCK (MLCK 480-516). The region was systematically analyzed by dividing it into fragments of two to six amino acids, each containing one or more basic residues, in order to map in detail the calmodulin binding site and the autoinhibitory region. It was observed that both calmodulin binding and autoinhibition are mediated by several different fragments of the regulatory sequence. Two nonoverlapping peptides, MLCK 480-493 and MLCK 494-504, are similar in potency in inhibiting the enzyme (IC50's of 2 and 6 microM, respectively). Larger fragments, combining multiple inhibitory regions, are more potent inhibitors. For example, MLCK 480-504 is extremely potent, with an IC50 of 13 nM. The calmodulin binding site and active site directed inhibitory regions overlap, but are not identical. Residues 505-512 are important only for calmodulin binding.

Amino Acid Sequence↗

PubMed1984

A calmodulin activated Ca2+-dependent K+ channel in human erythrocyte membrane inside-out vesicles.

The role of calmodulin in stimulating active calcium transport in the human red cell membrane is well documented. In contrast, efforts to characterize the effect of calmodulin on the Ca2+-dependent K+ channel in erythrocyte membranes have given rise to conflicting reports. These studies have indicated that experimental conditions may play a critical role in preserving the Ca2+-dependent K+ channels in erythrocyte inside-out vesicles. With these observations in mind, a double-labelling study of simultaneous active Ca2+ and passive Rb+ uptake in red-cell inside-out vesicles was undertaken. Addition of calmodulin and ATP to a suspension of inside-out vesicles containing 1 mM K+ caused a Ca2+-dependent increase in both the rate of active calcium transport and Rb+ uptake. The initial Rb+ isotope flux was increased 3-fold over the rate observed in the absence of calmodulin. The k1/2 for activation of K+ permeability was approx. 5 X 10(-7) M Ca2+ as compared to 10(-6) M Ca2+ for active Ca2+ transport. Addition of the calmodulin antagonists pimozide and chlorpromazine blocked calmodulin activation of the Ca2+-dependent K+ channel. The observation that activation of the K+ channel occurs at Ca2+ concentrations which are lower than those required for maximum stimulation of the calcium pump suggests that these processes are dependent on two states of the calmodulin molecule, characterized by a lower or higher amount of Ca2+ bound to calmodulin.

Adenosine Triphosphate↗

PubMed1984

Calcium-induced phosphorylations and [125I]calmodulin binding in renal membrane preparations.

Calcium-induced phosphorylated intermediates and calmodulin-binding proteins in membrane preparations from the renal cortex were analyzed by SDS-polyacrylamide gel electrophoresis at low pH, protein electroblotting and [125I]calmodulin overlay. Two calcium-induced phosphoproteins were found, with a molecular mass of 135 and 115 kDa, respectively. By comparing different preparations characterized by marker enzymes, it was shown that the 135 kDa phosphoprotein is localized in the basal-lateral fragment of the plasma membrane, whereas the 115 kDa phosphoprotein is more pronounced in preparations containing a high proportion of endoplasmic reticulum. A prominent calmodulin-binding protein comigrated with the 135 kDa phosphoprotein; there was no calmodulin binding to polypeptides in the molecular mass range of the 115 kDa phosphoprotein. Partial proteolysis by trypsin and the effect of 20 microM La2+ on the formation of phosphoproteins before and after trypsinization support the conclusion that the 135 kDa protein can be identified with the plasma membrane calcium pump, whereas the 115 kDa phosphoprotein is the phosphorylated intermediate of a different type of calcium pump probably originating from the endoplasmic reticulum. Calmodulin binding in renal membrane preparations analyzed on Laemmli-type slab gels revealed that there are many calmodulin-binding proteins in our preparations. We have identified one band with the renal calcium pump localized in the basal-lateral membrane. Another calmodulin-binding protein migrating at 108 kDa, is not localized in the basal-lateral membrane and could be one of the calmodulin-binding proteins originating from the cytoskeleton.

Animals↗

PubMed1985

Compound 48/80 and calmodulin modify the interaction of ATP with the (Ca2+ + Mg2+)-ATPase of red cell membranes.

Compound 48/80, an anti-calmodulin agent, reduces the maximum effect of ATP and does not affect the apparent affinity for ATP of the high-affinity site of the Ca2+-ATPase from calmodulin-bound membranes of human red cells. In the same preparation, 48/80 reduces more than 50-times the apparent affinity for ATP of the low-affinity site with little change in the maximum effect of the nucleotide at this site of the Ca2+-ATPase. The effects of compound 48/80 are independent of the concentration of Ca2+ between 30 and 200 microM. The apparent affinity of the low-affinity site of the Ca2+-ATPase for ATP is almost 100-fold less in calmodulin-stripped membranes than in calmodulin-bound membranes. In calmodulin-stripped membranes, exogenous calmodulin increases the apparent affinity for ATP up to the control values. These results indicate that apart from increasing the apparent affinity of the transport site for Ca2+, calmodulin also increases the apparent affinity of the regulatory site of the Ca2+-ATPase for ATP. Since this effect is exerted within the physiological ranges of ATP concentrations, it may participate in the physiological regulation of Ca2+ pumping by calmodulin.

Adenosine Triphosphate↗

PubMed1988

Inhibition of calcium release from skeletal muscle sarcoplasmic reticulum by calmodulin.

The effect of calmodulin on calcium release from heavy sarcoplasmic reticulum isolated from rabbit skeletal muscle was investigated with actively and passively calcium loaded sarcoplasmic reticulum vesicles and measured either spectrophotometrically with arsenazo III or by Millipore filtration technique. The transient calcium-, caffeine- and AMP-induced calcium release from actively loaded sarcoplasmic reticulum vesicles was reduced to 29%, 51% and 59% of the respective control value by 1 microM exogenous calmodulin. Stopped-flow measurements demonstrate that calmodulin reduces the apparent rate of caffeine-induced calcium release from actively loaded sarcoplasmic reticulum. The rate of calcium uptake measured in the presence of ruthenium red, which blocks the calcium release channel, was not affected by calmodulin or calmodulin-dependent phosphorylation of sarcoplasmic reticulum vesicles with ATP[S]. The rate of the calcium-, caffeine- and AMP-induced calcium release from passively loaded sarcoplasmic reticulum vesicles was reduced 1.4-2.0-fold by 1 microM exogenous calmodulin, i.e. the half-time of release was maximally increased by a factor of two, whilst calmodulin-dependent phosphorylation of a 57 kDa protein with ATP[S] had no effect. The data indicate that calmodulin itself regulates the calcium release channel of sarcoplasmic reticulum.

Adenosine Monophosphate↗

PubMed1983

The role of calmodulin in human renal cell carcinoma.

Calmodulin is a ubiquitous intracellular calcium binding protein which has been shown to be associated with cell cycling. Previous studies using animal tumor models have suggested a positive correlation between tumor calmodulin content and rate of tumor growth. We studied the role of calmodulin in renal cell carcinoma (RCC) cell lines and compared this with short term normal fetal kidney cell lines. The effects of calmodulin inhibition was determined using the calmodulin inhibitor W13 (Naphthalene-sulfonamide) and its less active partner W12. Cell size, calmodulin content and inhibition studies using W13 did not reveal any simple correlations for the RCC cell lines, although the RCC lines did have a higher content than the fetal kidney cell lines. Calmodulin content determination of RCC and normal adult kidney tissue failed to show any difference. We conclude that, contrary to previous reports using animal models, there is no simple relationship between tumor growth rates and calmodulin content for human RCC.

Adenocarcinoma↗

PubMed1985

Quantitation and significance of 125I-calmodulin binding to myosin light chain kinase and phosphorylase distributed on polyacrylamide gels.

Glycogen phosphorylase (a or b) binds 125I-calmodulin in a Ca2+-dependent manner, in the 125I-calmodulin overlay technique. This binding is quantitatively identical to 125I-calmodulin binding to myosin light chain kinase. In an in vitro assay, calmodulin stimulates phosphorylase activity at limiting concentrations of either glucose-1-phosphate or glycogen, but the Ka is 1000 fold higher than for the kinase, and is not Ca2+-dependent. Activation of phosphorylase, but not myosin light chain kinase, by calmodulin can be mimicked by troponin C or bovine serum albumin. These results demonstrate that the properties of calmodulin interaction with proteins can vary between the 125I-calmodulin technique and a functional assay of calmodulin effect on the same protein.

Animals↗

PubMed1987

Calmodulin-stimulated plasma membrane (Ca2+ + Mg2+)-ATPase: inhibition by calcium channel entry blockers.

Calcium channel entry blockers representing different structural classes were studied for their effects on human erythrocyte basal and calmodulin-stimulated (Ca2+ + Mg2+)-ATPase. Effects on the activity of (Mg2+)-ATPase and (Na+ + K+)-ATPase were also assessed. Of the four Ca2+ entry blockers tested, only verapamil and diltiazem specifically inhibited the calmodulin-stimulated (Ca2+ + Mg2+)-ATPase activity, the basal enzyme activity being unaltered by these drugs. Other membrane-associated ATPases were not affected. Calmodulin concentration effect curves showed the inhibition by verapamil (10(-3) M) and diltiazem (10(-3) M) to be non-competitive. This concentration inhibited the calmodulin-dependent increment (5.1 nM calmodulin) of the ATPase activity by 35 and 36% respectively. Similarly, both drugs inhibited the Ca2+-activation process of calmodulin-stimulated activity in a non-competitive manner, decreasing Vmax by 23 and 17% respectively. Basal (Ca2+ + Mg2+)-ATPase activity was not affected by verapamil or diltiazem at any calcium concentration. In contrast, cinnarizine non-specifically inhibited all four membrane ATPases including calmodulin-stimulated (Ca2+ + Mg2+)-ATPase activity at concentrations above 3 X 10(-6) M. Nifedipine was without effect on any of the four membrane ATPases. From this we conclude that certain calcium channel entry blockers can inhibit calmodulin-regulated plasma membrane Ca2+-pump ATPase. Therefore, this identifies an additional functional low affinity receptor in the plasma membrane for some of the calcium channel entry blockers.

Ca(2+) Mg(2+)-ATPase↗

PubMed1986

Calmodulin synthesis and accumulation during oogenesis and maturation of Xenopus laevis oocytes.

The calmodulin levels in stage 6 Xenopus oocytes averaged 89 +/- 24 (SD) ng/oocyte and had largely accumulated by stage 3 of oogenesis. From stage 3 to early stage 6, calmodulin levels did not increase further. However, in large stage 6 oocytes (greater than 1.25 mm diam) calmodulin levels again rose to a level as high as 121 ng/oocyte. Calmodulin levels did not change during the maturation of stage 6 oocytes and the results of measurements on animal and vegetal oocyte halves from control and mature oocytes showed no evidence of a redistribution of calmodulin during maturation. Measurements of calmodulin synthesis in stages 1 and 2 oocytes, stage 4 oocytes, and stage 6 oocytes indicated that calmodulin was being synthesized continuously during oogenesis and that the rate of synthesis increased during oogenesis. In stage 1 and 2 oocytes (combined), the synthesis rate was 3.5 pg/hr/oocyte; in stage 4 oocytes it was 48 pg/hr/oocyte, and in large stage 6 oocytes the rate had increased to 160 pg/hr/oocyte. These changes in the rates of synthesis were discussed as they relate to the pattern of calmodulin accumulation during oogenesis.

Animals↗

PubMed1990

Identity of the calmodulin-binding proteins in bovine lens plasma membranes.

Two bovine lens plasma membrane proteins have been identified that bind calmodulin in a Ca2(+)-dependent fashion. Electrophoretic analysis of lens membrane proteins photoaffinity-labeled with benzophenone[125I]calmodulin confirmed our previous observation [Louis, Johnson and Turnquist (1985) Eur. J. Biochem. 150, 271-8] that two major products are formed with Mr = 46 kDa and 36 kDa. Limited proteolysis of lens membrane proteins with chymotrypsin resulted in the formation of a 21-kDa-fragment that was derived from the hydrolysis of the major lens membrane protein MP26; this correlated with the loss of the 46-kDa complex, and the formation of a 41-kDa photoaffinity-labeled complex. Use of the [125I]calmodulin gel overlay procedure confirmed that the 46-kDa and 41-kDa photoaffinity-labeled complexes reflect the interaction of calmodulin with both MP26 and its 21-kDa chymotryptic fragment, respectively. Proteolysis of lens membranes with higher concentrations of chymotrypsin resulted in the hydrolysis of the 18-kDa protein which correlated with the generation of a 12-kDa fragment; this paralleled the loss of the 36-kDa photoaffinity labeled complex and the formation of a 28-kDa-complex. The [125I]calmodulin gel overlay procedure demonstrated that the 36-kDa and 28-kDa photoaffinity-labeled complexes reflect the interaction of calmodulin with the 18-kDa lens membrane protein and its likely 12-kDa chymotryptic fragment, respectively. Identification of these calmodulin-binding proteins suggests that MP26 and the 18-kDa membrane protein are likely candidates for the proposed calcium sensitive, calmodulin-dependent gating of lens fiber cell junctions.

Affinity Labels↗

PubMed1983

Effects of phospholamban phosphorylation catalyzed by adenosine 3':5'-monophosphate- and calmodulin-dependent protein kinases on calcium transport ATPase of cardiac sarcoplasmic reticulum.

To elucidate the role of 22000-dalton protein phospholamban, a putative regulator of Ca2+-dependent ATPase of cardiac sarcoplasmic reticulum, we examined the relationship between cyclic AMP- and calmodulin-dependent phosphorylation of phospholamban and their effects on ATPase activity and calcium transport of cardiac sarcoplasmic reticulum. Cardiac microsomes were incubated with [gamma-32P]ATP or unlabeled ATP, catalytic subunit of cyclic AMP-dependent protein kinase and/or exogenous calmodulin, and subsequently assayed for ATPase activity and calcium uptake by cardiac sarcoplasmic reticulum. Cyclic AMP-dependent phosphorylation of phospholamban was independent of Ca2+, whereas calmodulin-dependent phosphorylation of phospholamban was dependent on Ca2+ within a range between 0.2 and 50 microM. Cyclic AMP- and calmodulin-dependent phosphorylation of phospholamban occurred independently; when both kinases were operative, the amounts of phosphorylation were additive. Under these conditions, the phosphoproteins formed by cyclic AMP- and calmodulin-dependent protein kinases electrophoretically migrated as 11000-dalton components when sodium dodecyl sulfate-solubilized phosphoproteins were boiled prior to polyacrylamide gel electrophoresis. The ATPase activity was stimulated by either cyclic AMP- or calmodulin-dependent phosphorylation of phospholamban at Ca2+ concentrations up to 2 microM. The extents of stimulation of ATPase activity were additive when both types of phosphorylation were functional. Calcium uptake was similarly augmented by cyclic AMP- and/or calmodulin-dependent phosphorylation of phospholamban. These results indicate that Ca2+-dependent ATPase and calcium transport of cardiac sarcoplasmic reticulum are regulated by phospholamban phosphorylation catalyzed by cyclic AMP- and calmodulin-dependent protein kinases, thus suggesting a dual role of phospholamban in active calcium transport.

Biological Transport, Active↗

PubMed1989

Structural organization of multiple rat calmodulin genes.

Elsewhere, we have reported the structure of a rat calmodulin gene and two distinct rat calmodulin cDNAs, pRCM1 and pRCM3. Here, I report the cloning and sequencing of the third calmodulin cDNA (pRCM4) and two additional rat calmodulin genes. The original calmodulin gene is named CaM I (pRCM1) and the newly discovered calmodulin genes are named CaM II (pRCM3) and CaM III (pRCM4). CaM II spans about 10 x 10(3) base-pairs and consisted of five exons, while CaM III spans about 7.2 x 10(3) base-pairs and consisted of six exons. One of the introns (intron 3) observed in CaM I and CaM III is lost in CaM II. Otherwise, the intron/exon organization of these genes is exactly the same. In all calmodulin genes, the first intron separates the initiation codon (ATG) from the coding region of the protein. Northern blotting showed that CaM I is transcribed primarily into 1.7 x 10(3) base-pair mRNA in various tissues examined and 4.0 x 10(3) base-pair mRNA mainly in skeletal muscle, CaM II is transcribed into 1.4 x 10(3) base-pair mRNA almost exclusively in brain and CaM III is transcribed predominantly into 2.3 x 10(3) base-pair mRNA and faintly into 1.0 x 10(3) base-pair mRNA mainly in skeletal muscle and brain. DNA sequences in the promoter-regulator regions of these genes are partly homologous but essentially distinct and possess a number of direct repeats, palindromes and feasible stem-loop structures. Together with these, I report here the structures of the third and fourth calmodulin retropseudogenes.

Animals↗

PubMed1987

Calmodulin content in human brain tumors.

Using a radioimmunoassay method, the particulate and soluble calmodulin levels were determined in biopsied specimens from normal human brain and from various human brain tumors. Both in normal and pathological tissues the major portion of calmodulin was revealed in the cytosol. The chromatographic elution profiles of calmodulin obtained from soluble and particulate fractions of the same specimen were identical, thus suggesting an identity of the supernatant and particulate form of calmodulin. In all the examined oncotypes, the calmodulin content was lower than in normal extracts and this biochemical feature could not have been correlated with the degree of malignancy of the neoplasia. Furthermore, the translocation of calmodulin from the particles to the cytoplasm, reported in other rapidly growing tumors, lacks in human cerebral ones. Our findings indicate that in human brain oncotypes the calmodulin distribution is quite different from that found in tumors taken from other tissues, where its level is increased and a positive correlation between calmodulin concentration and growth rate of neoplastic tissue has been revealed.

Adult↗

PubMed1989

Increased covalent binding of acetaldehyde to calmodulin in the presence of calcium.

The regulatory protein, calmodulin, undergoes major conformational changes in response to changes in intracellular calcium concentration. Furthermore, calmodulin has been reported to have lysine residues which markedly increase their reactivity toward electrophilic substances in the calcium-loaded state. We found that calmodulin formed two to three times more stable adducts with acetaldehyde in the calcium-loaded state as compared to the calcium-free state. Competition-binding studies showed that calmodulin could preferentially compete with albumin for acetaldehyde in the presence, but not in the absence, of calcium. When calmodulin was in the calcium-loaded state, trifluoperazine, an inhibitor of calmodulin activity, significantly decreased the stable binding of acetaldehyde to the protein, whereas in the calcium-free state, minimal effects on binding were observed. Since calmodulin is involved in regulation of multiple important processes in the cell, it is possible that acetaldehyde-calmodulin adducts could contribute to liver injury by perturbation of calcium-dependent homeostatic mechanisms within the hepatocyte.

Acetaldehyde↗

PubMed1990

Effect of anti-calmodulin agents on vasopressin release in vitro to depolarization and calcium ionophore.

Calmodulin has been implicated in transducing the effects of Ca2+ on synaptic transmission and hormone release, including osmotically-stimulated vasopressin (AVP) release. If the anti-calmodulin agents block AVP release secondary to inhibition of Ca2(+)-calmodulin interactions, these drugs should inhibit AVP release to stimuli increasing Ca2+ influx via different mechanisms. Hypothalamo-neurohypophysial complexes (HNC) were exposed to ionomycin, Bay K 8644, or veratridine either alone, with any one of three distinct chemical classes of anti-calmodulin agent, or with a Ca2+ channel antagonist. All the anti-calmodulin agents impaired AVP release to ionomycin, while Ca2+ channel blockade did not. Conversely, Ca2+ channel antagonism completely blocked AVP release in response to Bay K 8644, but the anti-calmodulin agents had no effect. None of the inhibitors prevented veratridine-induced AVP release. These results are consistent with the hypothesis that the anti-calmodulin agents tested inhibit AVP release by their membrane stabilizing properties rather than by antagonizing Ca2(+)-calmodulin in HNC. Depolarization initiated by Na+ influx may stimulate Na(+)-Ca2+ exchange by a mechanism independent of slow Ca2+ channels as well.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1986

Calmodulin regulation of the cholinergic receptor in the rat heart during ontogeny and senescence.

The contents of calmodulin and cholinergic muscarinic receptor binding sites in the hearts of fetal, adult and aged rats have been examined. A biphasic pattern of calmodulin development was observed. A relatively high level of calmodulin appeared on gestational days 14-15 followed by a steady but significant decrease at birth and during the first week of postnatal life. The level of calmodulin then increased significantly during the first month followed by a decrease at 6 and 26 months of age. Calmodulin contents were significantly higher in the atrium than in the ventricle in the age groups of 1-26 months. The number of [3H]QNB binding sites showed a steady increase during the gestational periods studied, reaching a peak at 9 days after birth and followed by a significant (P less than 0.05) decline at 6 and 26 months of age. A good correlation between the levels of [3H]QNB binding and calmodulin was observed from day 9 of the postnatal period to 26 months of age. In the presence of calcium, calmodulin induced a dose-dependent receptor binding loss in the hearts of postnatal, young adult and aged rats under phosphorylating conditions. These findings support the suggestion that calmodulin may regulate cholinergic functions during ontogeny and senescence.

Aging↗