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PubMed1989

Calmodulin selectively modulates the guanylate cyclase activity by repressing the lipid phase separation temperature in the inner half of the bilayer of rat brain synaptosomal plasma membranes.

The association of [125I-]calmodulin with rat brain synaptosomal plasma membranes, when incubated for 1 h at 25 degrees in the presence or in absence of 20 microM Ca2+, follows a sigmoid path with a Hill coefficient h = 1.79 +/- 0.12 and h = 1.72 +/- 0.11, respectively. The total association of calmodulin with the membrane increased approx. 60%-80% at all the range of calmodulin concentrations used in the presence of 20 microM Ca2+. A three fold increase of guanylate cyclase activity was shown in the presence of low concentrations of calmodulin (up to 10 nM); higher concentrations (up to 40 nM) however, led to a progressive inhibition of the enzyme activity with respect to maximal stimulation. Calmodulin increased the lipid fluidity of synaptosomal plasma membranes labeled with 1,6-diphenyl-1,3,5-hexatriene (DPH), as indicated by the steady-state fluorescence anisotropy [(ro/r)-1]-1. Arrhenius-type plots of [(ro/r)-1]-1 indicated that the lipid separation of the membrane at 22.7 +/- 1.2 degrees was perturbed by calmodulin such that the temperature was reduced to 16.3 +/- 0.9 degrees and 15.5 +/- 0.8 degrees in the absence or in the presence of 20 microM Ca2+. Arrhenius plots of guanylate cyclase and acetylcholinesterase activities exhibited break points at 26.7 +/- 1.4 degrees and 22.3 +/- 1.0 degrees in control synaptosomal plasma membranes, respectively. The break point for the guanylate cyclase was reduced to 16.3 +/- 0.9 degrees in calmodulin treated synaptosomal plasma membranes whereas that of acetylcholinesterase remained unaffected (21.1 +/- 0.9 degrees).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1989

Inhibition of calmodulin and protein kinase C by amiodarone and other class III antiarrhythmic agents.

Class III antiarrhythmic agents may prolong refractoriness via modulation of ion channels, which may be sensitive to Ca2+ regulatory proteins or enzymes. Accordingly, the purpose of this study was to quantitate the effects of several structurally diverse class III antiarrhythmic agents on calmodulin-regulated enzymes and protein kinase C activity, and to evaluate the ability of these agents and known calmodulin antagonists to prolong cardiac refractoriness in vivo. The rank order of potency (IC50;microM) of selected class III antiarrhythmic agents and reference calmodulin antagonists as inhibitors of calmodulin-regulated phosphodiesterase activity were: calmidazolium (0.12 microM) greater than amiodarone (0.62 microM) greater than desethylamiodarone (1.5 microM) greater than trifluoperazine (4.3 microM), bepridil (5 microM) greater than W-7 (7.5 microM), clofilium (13 microM). Similar concentration-related inhibition was evident in a second calmodulin-regulated system, inhibition of myosin light-chain phosphorylation and superprecipitation of arterial actomyosin. Sotalol and tetraethylammonium were inactive at 100 microM. Protein kinase C activity was also inhibited by some of these agents; desethylamiodarone (IC50 = 11 microM) was more potent than the reference agent, H-7 (IC50 = 79 microM), or amiodarone (38% inhibition at 100 microM) and clofilium (32% inhibition at 100 microM). In vivo, the minimally effective doses required to increase ventricular effective refractory periods in paced guinea pigs were (in mg/kg) bepridil, sotalol [1] greater than clofilium [3] greater than amiodarone [10] greater than W-7, desethylamiodarone [20]. No changes in refractory period were noted with maximum testable doses of calmidazolium or trifluoperazine. These studies show that some, but not all, class III antiarrhythmic agents are effective and potent calmodulin antagonists or protein kinase C inhibitors. Moreover, some calmodulin antagonists are effective at prolonging refractoriness in vivo. However, a lack of correlation between these agents suggests that these mechanisms are not solely responsible for the prolongation of refractoriness of all class III agents.

Actomyosin↗
PubMed1993

Calmodulin mediates melatonin cytoskeletal effects.

In this article, we review the data concerning melatonin interactions with calmodulin. The kinetics of melatonin-calmodulin binding suggest that the hormone modulates cell activity through intracellular binding to the protein at physiological concentration ranges. Melatonin interaction with calmodulin may allow the hormone to modulate rhythmically many cellular functions. Melatonin's effect on tubulin polymerization, and cytoskeletal changes in MDCK and N1E-115 cells cultured with melatonin, suggest that at low concentrations (10(-9) M) cytoskeletal effects are mediated by its antagonism to Ca2+-calmodulin. At higher concentrations (10(-5)M) non-specific binding of melatonin to tubulin occurs thus overcoming the specific melatonin antagonism to Ca2+-calmodulin. Since the structures of melatonin and calmodulin are phylogenetically well preserved, calmodulin-melatonin interaction probably represents a major mechanism for regulation and synchronization of cell physiology.

Animals↗
PubMed1985

Calmodulin in mast cells and its role in histamine secretion.

Calmodulin content and distribution in rat peritoneal mast cells was determined by radioimmunoassay. Isolated pure mast cells were disrupted by sonication and the total calmodulin content and its distribution were determined. Calmodulin bound to the membranes was released by heating with 0.1% Lubrol PX to 95 degrees C for 5 min. The total calmodulin content of mast cells was found to be 160 +/- 14 ng/10(6) cells (9.4 +/- 0.82 pmoles/10(6) cells). The highest amount (68%) was present in the supernatant representing the cytosol. The next highest amount (26%) was found in the composite fraction consisting of mitochondria, endoplasmic reticulum, Golgi vesicles and plasma membrane (100,000 g pellet). The mast cell granules contained 4% of the total calmodulin. Trifluoperazine (TFP) was used as an antagonist to explore the role of calmodulin in histamine secretion. At 10 microM concentration, TFP caused a negligible spontaneous histamine release by its membrane effect. TFP (10 microM) inhibited histamine release by all the three secretagogues used, but the degree of inhibition varied: 60% with antigen, 40% with compound 48/80 and 20% with ionophore A23187. It is suggested that the TFP effect is due to calmodulin-antagonism and interference with the activation of enzymes, essential to the secretory process.

Animals↗
PubMed1996

Inhibition of calmodulin expression prevents low-pH-induced gap junction uncoupling in Xenopus oocytes.

The relationship among intracellular pH (pHi), -log10 intracellular Ca2+ concentration (pCai) and gap junctional conductance, the participation of Ca2+ stores, and the role of calmodulin in channel regulation have been studied in Xenopus oocytes, expressing the native connexin (Cx38), exposed to external solutions bubbled with 100% CO2. The time courses of pHi [measured with 2',7'-bis(2-carboxyethyl)-5,6-carboxyfluorscein (BCECF)], pCai (measured with the membrane-associated fura-C18) and junctional conductance (measured with a double voltage-clamp protocol) were compared. The data obtained confirm previous evidence for a closer relationship of junctional conductance with pCai than with pHi. Evidence for an inhibitory effect of intracellularly injected ruthenium red or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) on CO2-induced uncoupling, coupled to negative results with Ca2+-free external solutions, point to a low-pHi -induced Ca2+ release from internal stores, likely to be primarily mitochondria. The hypothesis proposing a participation of calmodulin in channel gating was tested by studying the effects of calmodulin expression inhibition by intracellular injection of oligonucleotides antisense to the two calmodulin mRNAs expressed in the oocytes. Calmodulin mRNA was permanently eliminated in 5h. The oocytes injected with the antisense nucleotides progressively lost the capacity to uncouple with CO2 within 72 h. The effect of CO2 on junctional conductance was reduced by approximately 60% in 24 h, by approximately 76% in 48 h and by approximately 93% in 72 h. Oocytes that had lost gating sensitivity to CO2 partially recovered gating competency following calmodulin injection. The data suggest that lowered pHi uncouples gap junctions by a Ca2+- calmodulin-mediated mechanism.

Animals↗
PubMed1985

Calmodulin in various insulin secreting cell types.

The involvement of the Ca2+ binding protein, calmodulin, in the regulation of insulin release was studied. Calmodulin was measured in isolated rat islets, rat insulinoma cells, the insulin secreting cell line (RINm5F) and in islets isolated from normal and diabetic Chinese hamsters. Total content of calmodulin was determined by a radioimmunoassay using a rabbit anti-calmodulin serum and was found to lie in the range of 4 to 7 micrograms/ml protein. When rat islets were maintained in tissue culture for 6 days at 2.8 or 8.3 mM glucose, the content of calmodulin of the two groups was similar. Likewise there was no difference in calmodulin content between islets from normal and diabetic hamsters. This study suggests that a variation of the total cellular calmodulin does not play a role in the process of insulin secretion.

Animals↗
PubMed2004

Platelet calmodulin levels in adolescent idiopathic scoliosis (AIS): can they predict curve progression and severity? Summary of an electronic focus group debate of the IBSE.

There is no generally accepted scientific theory for the etiology of idiopathic scoliosis. As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate of extant knowledge on important topics. This has been designated as an on-line Delphi discussion. The text for this EFG was written by Professor Thomas G Lowe MD and drawn from research carried out by himself and his co-workers on platelet calmodulin levels in patients with adolescent idiopathic scoliosis. To explain the relationship of platelet calmodulin levels to scoliosis curve changes in AIS brought about spontaneously, by brace treatment, or surgery Dr Lowe attributes the platelet calmodulin changes to paraspinous muscle activity and suggests that the calmodulin acts as a systemic mediator of tissues having a contractile system (actin and myosin). Controversy includes: 1) the lack of normal data and the large variability in baseline levels of platelet calmodulin, necessitating the use of the AIS subjects as their own controls; 2) calmodulin is not usually used as a marker of platelet activation; 3) whether the platelet calmodulin changes which appear to reflect an abnormality of a portion of the spine are related to local and/or regional changes in muscles, nervous system, or immature vertebrae. What is not controversial is the need for more research on platelets and the immature deforming skeleton in relation to etiology and prognosis.

Adolescent↗
PubMed1988

Calmodulin-stimulated cyclic nucleotide phosphodiesterases in plasma membranes of bovine epididymal spermatozoa.

Cyclic nucleotide phosphodiesterase in the plasma membranes of bovine epididymal spermatozoa was stimulated by added Ca2+ and calmodulin. The rate of hydrolysis and responsiveness toward calmodulin was greater for cAMP than for cGMP. The kinetic analysis of the activity revealed two forms of phosphodiesterase with apparent Km values of 7.5 and 95 microM for cAMP. Calmodulin stimulated both of the activities by increasing the Vmax without affecting the Km's. The activity response with respect to Ca2+ concentration appears to be biphasic in both the absence and presence of added calmodulin. Trifluoperazine inhibited the Ca2+- and calmodulin-sensitive enzyme activity in a dose-dependent manner. The calmodulin-stimulated phosphodiesterase activity in the sperm plasma membranes can be solubilized and absorbed to a Calmodulin-Sepharose affinity column in the presence of Ca2+.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1981

Phenothiazines and related compounds disrupt mitochondrial energy production by a calmodulin-independent reaction.

Phenothiazines and related compounds bind to mitochondrial membranes in approximate proportion to their affinities for calmodulin. Penfluridol (16 microM), pimozide (20 microM), or trifluoperazine (66 microM) completely inhibit ADP-stimulated respiration in isolated rat liver mitochondria, but exert no effect on either uncoupler- or Ca2+-stimulated respiration. The inhibition of ADP-stimulated respiration results from inhibition of the oligomycin-sensitive ATPase. Inhibition of the ATPase does not involve interaction of phenothiazine with calmodulin. The addition of calmodulin with or without calcium to mitochondrial inner membrane preparations has no effect on ATPase activity. The addition of EGTA and the ionophore A23187 prior to the addition of phenothiazine does not prevent the phenothiazine-induced inhibiton of the ATPase. Measurements of inner membrane calmodulin content by gel electrophoresis or cyclic nucleotide phosphodiesterase activation are negative. Despite the absence of calmodulin in the inner membrane preparations, 12.5 nmol trifluoperazine bind per 100 microgram of membrane protein with an association constant, K, of 6.5 . 10(4) M-1. We conclude that calmodulin-binding neuroleptic agents, when added to whole cells, have the potential to disrupt mitochondrial energy production by a reaction which apparently does not involve a phenothiazine-calmodulin interaction.

Adenosine Triphosphatases↗
PubMed1980

Regulatory interaction between calmodulin and ATP on the red cell Ca2+ pump.

The interactions between calmodulin, ATP and Ca2+ on the red cell Ca2+ pump have been studied in membranes stripped of native calmodulin or rebound with purified red cell calmodulin. Calmodulin stimulates the maximal rate of (Ca2+ + Mg2+)-ATPase by 5-10-fold and the rate of Ca2+-dependent phosphorylation by at least 10-fold. In calmodulin-bound membranes ATP activates (Ca2+ + Mg2+)-ATPase along a biphasic concentration curve (Km1 approximately 1.4 microM, Km2 approximately 330 microM), but in stripped membranes the curve is essentially hyperbolic (Km approximately 7 microM). In calmodulin-bound membranes Ca2+ activates (Ca2+ + Mg2+)-ATPase at low concentrations (Km less than 0.28 microM) in stripped membranes the apparent Ca2+ affinities are at least 10-fold lower. The results suggest that calmodulin (and perhaps ATP) affect a conformational equilibrium between E2 and E1 forms of the Ca2+ pump protein.

Adenosine Triphosphate↗
PubMed1986

The activation of phosphatase activity of the Ca2+-ATPase from human red cell membranes by calmodulin, ATP and partial proteolysis.

Depending on the assay conditions, the ability of the Ca2+-ATPase from intact human red cell membranes to catalyze the hydrolysis of p-nitrophenylphosphate is elicited by either calmodulin or ATP. The response of the phosphatase activity to p-nitrophenylphosphate, ATP, Mg2+ and K+ is the same for the activities elicited by ATP or by calmodulin, suggesting that a single process is responsible for both activities. In media with calmodulin, high-affinity activation is followed by high-affinity inhibition of the phosphatase by Ca2+ so that the activity becomes negligible above 30 microM Ca2+. Under these conditions, addition of ATP leads to a large decrease in the apparent affinity for inhibition by Ca2+. In membranes submitted to partial proteolysis with trypsin, neither calmodulin nor Ca2+ are needed and phosphatase activity is maximal in media without Ca2+. This is the first report of an activity sustained by the Ca2+-ATPase of red cell membranes in the absence of Ca2+. Under these conditions, however, ATP still protects against high-affinity inhibition by Ca2+. These results strongly suggest that during activation by calmodulin, Ca2+ is needed only to form the calmodulin-Ca2+ complex which is the effective cofactor. Protection by ATP of the inhibitory effects of Ca2+ and the induction of phosphatase activity by ATP + Ca2+ suggests that activation of the phosphatase by Ca2+ in media with ATP requires the combination of the cation at sites in the ATPase. Results can be rationalized assuming that E2, the conformer of the Ca2+-ATPase, is endowed with phosphatase activity. Under this assumption, either the calmodulin-Ca2+ complex or partial proteolysis would elicit phosphatase activity by displacing the equilibrium between E1 and E2 towards E2. On the other hand, ATP + Ca2+ would elicit the activity by establishing through a phosphorylation-dephosphorylation cycle a steady-state in which E2 predominates over other conformers of the ATPase.

Adenosine Triphosphate↗
PubMed1994

Calmodulin modulates protein 4.1 binding to human erythrocyte membranes.

Calmodulin, an abundant protein in the red cell cytosol, exerts its effects on erythrocyte membrane properties via interactions with numerous proteins. To evaluate whether calmodulin might regulate association of protein 4.1 with one of its integral membrane protein anchors, protein 4.1 binding to inside-out erythrocyte membrane vesicles (IOVs) in the presence and absence of calmodulin and Ca2+ was examined. Ca2+ plus calmodulin was found to competitively inhibit protein 4.1 association with IOVs with a Ki of 1.4 microM and a maximal inhibition of 83%. In the absence of Ca2+, calmodulin still reduce protein 4.1 binding by 43%, consistent with the known Ca2+ independent association of calmodulin with protein 4.1. Ca2+ alone had no effect on protein 4.1-membrane interactions. Digestion studies revealed that both band 3 and glycophorin sites were similarly affected by calmodulin competition, suggesting all major protein 4.1 anchors are potentially regulated. In light of other data showing regulation of the same interactions by phosphoinositides, protein kinases, and the concentration of free cytosolic 2,3-diphosphoglycerate, it can be argued that association of protein 4.1 with integral protein anchors constitutes one of the more sensitively regulated interactions of the membrane.

Binding Sites↗
PubMed1984

Calcium regulation of phospholipase A2 is independent of calmodulin.

There are conflicting data in the literature as to whether or not the Ca2+ activation of phospholipase A2 is mediated by the calcium binding protein calmodulin. In the present study the membrane-bound phospholipase A2 enzymes in rat and human platelets were shown to be absolutely Ca2+ dependent but were not stimulated by the addition of calmodulin. A partially purified phospholipase A2 from rat platelet membrane, which contained little endogenous calmodulin, also was not stimulated by calmodulin addition. Both isolated and membrane-bound phospholipase A2 were inhibited by the non-specific calmodulin antagonist trifluoperazine but the inhibition was not overcome by adding calmodulin. There was thus no evidence from these studies that phospholipase A2 is calmodulin regulated.

Animals↗
PubMed1983

Effects of local anesthetics on calmodulin-dependent guanylate cyclase in the plasma membrane of Tetrahymena pyriformis.

A highly purified preparation of Tetrahymena calmodulin activated a membrane-bound guanylate cyclase by more than 40-fold. This activation of guanylate cyclase by calmodulin was inhibited completely by local anesthetics such as dibucaine, tetracaine, lidocaine and procaine at concentrations that had no appreciable effect on the activities of basal guanylate cyclase (without calmodulin) and adenylate cyclase. The inhibition by dibucaine of calmodulin-mediated activation of the enzyme activity was not reversed by calcium but was partially overcome by increasing the concentration of calmodulin. Kinetic analysis of local anesthetic-induced inhibition of activation of guanylate cyclase demonstrated a mixed type of antagonism. These results suggest the possibility that the inhibition of calmodulin-dependent guanylate cyclase resulted, in part, from interaction of the drugs with calmodulin.

Adenylyl Cyclases↗
PubMed1985

Interaction of DDT and pyrethroids with calmodulin and its significance in the expression of enzyme activities of phosphodiesterase.

To understand the significance of the inhibitory action of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and pyrethroid insecticides on calmodulin, a universal Ca2+ binding protein, a bovine heart phosphodiesterase-calmodulin system was studied. It was found that, at concentrations of less than 10(-5) M, the inhibitory action of DDT of the phosphodiesterase was due entirely to its action on calmodulin alone. Cypermethrin was less potent than DDT, but it also affected only calmodulin. Permethrin was the most potent inhibitor affecting calmodulin and, to a lesser extent, phosphodiesterase. The inhibitory action of these insecticides on calmodulin raises a possibility that many unsuspected Ca2+-related systems are being affected by these insecticidal chemicals, as calmodulin is known to play vital roles in many biological reactions dependent upon Ca2+. These include modulation of phosphodiesterase, neurotransmitter release, adenylate cyclase, Ca2+-dependent protein kinase, myosine light chain kinase and various membrane phosphorylation systems.

Animals↗
PubMed1994

A survey of human breast cancer sensitivity to growth inhibition by calmodulin antagonists in tissue culture.

We compared the ability of N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide (W-13), a calmodulin antagonist, to inhibit the growth of seven human breast cancer cell lines in tissue culture, to determine whether drug sensitivity was related to estrogen receptor (ER) status, tamoxifen resistance (tamr), or levels of calmodulin activity. We examined three ER+ (estrogen receptor-positive) cell lines (MCF-7, ZR-75-1B, and T47D), two ER+/tamr lines (LY2 and RR), and two ER- (estrogen receptor-negative) cell lines (MDA-MB-231 and MDA-MB-435). There was no difference in the inhibition of cell growth by W-13 in MCF-7 cells and the two tamr MCF-7 cell derivatives, LY2 and RR. In addition, the sensitivity to W-13 did not appear to be related to ER status. Although the mean Ki of the five ER+ cell lines (31 microM) was somewhat higher than the mean Ki of the two ER- cell lines (23 microM), the two cell lines most sensitive to W-13 were the ER+ T47D cells (Ki 15 microM) and the ER- MDA-MB-435 cells (Ki 10 microM). Calmodulin activity was measured in three representative cell lines, MCF-7, LY2, and MDA-MB-435. Calmodulin levels were higher in the most sensitive cell line (MDA-MB-435, 2.7 ng calmodulin/micrograms protein) than in the two less sensitive cell lines, MCF-7 and LY2 (1.3 and 1.6 ng calmodulin/micrograms protein, respectively). However, the MCF-7, LY2, and MDA-MB-435 cells were equally sensitive to another specific calmodulin antagonist, calmidazolium. We conclude that neither ER status, tamoxifen resistance, nor levels of calmodulin activity predict the sensitivity of human breast cancer cell lines to growth inhibition in tissue culture by calmodulin antagonists.

Breast Neoplasms↗
PubMed1988

Calmodulin distribution in peripheral nerve: an EM immunocytochemical study.

We used electron microscopic immunocytochemistry to study the distribution of calmodulin in rat sciatic nerve. Calmodulin immunoreactivity was found throughout the axoplasmic matrix, but particularly along microtubules. Schwann cell cytoplasm and nuclei demonstrated immunoreactivity, while compact myelin did not. There was particularly intense immuno-gold deposition within Schmidt Lanterman clefts. At the nodes of Ranvier, calmodulin appeared preferentially in the paranodal region, along the apposition of the axolemma to the paranodal loops of myelin and extending into the paranodal loops. The presence of calmodulin immunoreactivity along microtubules supports biochemical and pharmacological evidence of calmodulin involvement in regulating the assembly and phosphorylation of microtubules, and in fast axonal transport along microtubules. The co-localization of paranodal calmodulin immunoreactivity with Ca-ATPase activity demonstrated cytochemically (Mata et al., Brain Research, in press) supports the notion that the paranodal Ca-ATPase activity may be regulated by calmodulin, and agrees with the in vitro biochemical evidence for Ca-ATPase of other cells.

Animals↗
PubMed1988

Prostaglandin E2 releases luteinizing hormone-releasing hormone from the female juvenile hypothalamus through a Ca2+-dependent, calmodulin-independent mechanism.

Prostaglandin E2 (PGE2) has been implicated as a mediator of norepinephrine-induced luteinizing hormone-releasing hormone (LHRH) release from the hypothalamus. The present experiments were undertaken to examine the hypothesis that mobilization of Ca2+ from intracellular stores and cyclic AMP (cAMP) formation are involved in this effect. Incubation of median eminence (ME) nerve terminals from juvenile rats in Ca2+-free Krebs-Ringer bicarbonate buffer reduced, but failed to prevent the stimulatory effect of PGE2 on LHRH release. None of 5 calmodulin antagonists or a blocker of calmodulin-dependent kinase affected the LHRH response to PGE2. In contrast, inhibition of intracellular Ca2+ mobilization with TMB-8 or dantrolene in Ca2+-free medium prevented the LHRH releasing effect of PGE2. Similarly to PGE2, the stimulatory effect of the Ca2+ ionophore A 23187 on LHRH release was not affected by inhibition of calmodulin activity. This, however, blocked the increase in PGE2 formation induced by the ionophore. PGE2 evoked a dose-related increase in cAMP accumulation in Ca2+-containing medium and this effect was inhibited both by blockers of intracellular Ca2+ mobilization and by calmodulin antagonists. Surprisingly, removal of extracellular Ca2+ increased basal cAMP levels in the incubation medium without affecting LHRH release; PGE2 induced a further increase in cAMP which was prevented by inhibition of intracellular Ca2+ translocation. Stimulation of adenylate cyclase activity with forskolin (F) resulted in similar increases in cAMP levels both in the presence and absence of extracellular Ca2+. However, F failed to evoke LHRH release in Ca2+-free medium. The results indicate that: (a) the stimulatory effect of PGE2 on LHRH release involves mobilization of intracellular Ca2+ but not the participation of calmodulin; (b) the formation of PGE2 itself is calmodulin-dependent; (c) PGE2 stimulates cAMP formation through a calmodulin-dependent mechanism that requires translocation of intracellular (membrane?) Ca2+; (d) the cAMP system of a population of nerve terminals different from that responsive to PGE2 is normally subjected to a Ca2+-dependent inhibitory control; and (e) although PGE2 is a potent stimulator of cAMP formation in the ME and endogenously produced cAMP can induce LHRH release, in the absence of extracellular Ca2+ PGE2 stimulates LHRH release in a cAMP-independent manner.

Animals↗