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In Dictyostelium there are multiple prestalk cell types that have a complex pattern of directed cell movement during slug formation and culmination. Three extracellular signals, cyclic AMP, DIF and ammonia, control cell type differentiation. Recently there has been considerable progress in understanding their modes of action and interaction.
Vertebrate retina rhythmically produces melatonin, a hormone involved in the regulation of several intraocular processes cued by environmental lighting conditions. Calcium ions play an important role in the induction process of serotonin N-acetyltransferase (NAT), a key regulatory enzyme in melatonin biosynthetic pathway. The physiological, i.e. nocturnal, increase of NAT activity in the retina depends on transmembrane transport of Ca2+ through the L-type of voltage-sensitive calcium channels. It is suggested that Ca2+ may regulate NAT activity indirectly, by affecting the intracellular cyclic AMP content, which is, in turn, critical in the regulation of melatonin biosynthesis. The mode and mechanisms of Ca2+ action on processes governing melatonin formation in the retina are discussed.
In light of previous studies which have implicated prostaglandin (PG) formation as a link in ACTH-induced steroid production by isolated cat adrenocortical cells, experiments were carried out to provide additional information regarding the role of PGs in adrenal steroidogenesis and their interactions with calcium and cyclic AMP. Perfusion of cat adrenal glands with Locke's solution plus beta(1-24)-ACTH resulted in an immediate increase in PGF2alpha release, which rapidly declined to basal levels after the stimulus was withdrawn. In contrast, maximal rates of steroid release were manifest some 30 min after removal of ACTH. ACTH and its onitrophenyl sulfenyl derivative (NPS-ACTH) increased PG (PGF2alpha and PGE2) and steroid release by trypsin-dispersed cat cortical cells, but NPS-ACTH, unlike ACTH, did not augment cortical cyclic AMP levels. In this same preparation, indomethacin completely blocked ACTH and NPS-ACTH facilitated PGF2alpha and PGE2 release but failed to suppress steroid release markedly. Calcium-deprivation blocked PG and steroid release evoked by these two polypeptides, and depressed PG release elicited by monobutyryl cyclic AMP (bcAMP) without affecting steroid release. These experiments offer additional evidence to support the concept that PGs play a role in the mode of action of ACTH; however, they do not appear to be obligatory intermediates in the steroidogenic process. The importance of calcium in regulating PG formation is discussed with special regard for the idea that this cation has a direct action on the enzyme systems which control PG synthesis.
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The mechanism by which the metabolic effects of insulin are transmitted is yet to be resolved. Second messengers mediating the action of insulin have been proposed and recently an insulin-dependent, peptide-like, heat- and acid-stable substance (Mr approx. 1000-3000) released from plasma membranes has been described which regulates the activity of key enzymes such as pyruvate dehydrogenase by altering its state of phosphorylation. It has been suggested that this material is the elusive second messenger of insulin and its discovery, generation, properties, isolation and mode of action are reviewed.
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The two New Zealand tea-tree oils, Manuka (Leptospermum scoparium J.R. et G. Forst) and Kanuka (Kunzea ericoides (A. Rich) J. Thompson), Myrtaceae have been used as folk medicines for treating diarrhoea, colds and inflammation but their pharmacological action has not been investigated. Their mode of action was therefore studied on the field-stimulated guinea-pig ileum. Both Manuka and Kanuka oils induced a spasmolytic effect but Kanuka produced an initial contraction. The spasmolytic action of both oils was the result of a post-synaptic mechanism. Action involving adrenoceptors or cGMP was not considered likely, neither did the oils behave like calcium- or potassium-channel openers. There is some evidence that Manuka acts through cAMP whereas the mode of action of Kanuka is as yet undetermined. The results indicate that the use of these oils as relaxants in aromatherapy might be valid, although their mode of action is not identical.
Primary cultures of mouse adrenocortical tumors provide a sensitive system for investigating the effects of the enterotoxin of the V. cholerae (choleragen) on cyclic-AMP metabolism in the intact cell. Like ACTH, the toxin stimulates the synthesis and release of steroids from these cells but its mode of action differs from that of ACTH. The steroidogenic response to ACTH is immediate and of limited duration. The initial rate of steroidogenesis is the highest. In contrast, the steroidogenic response to choleragen is preceded by a 30-240 minute lag period which is inversely related to the concentration of the toxin. Whereas prolongation of the response to a single dose of ACTH requires hormone concentrations above those producing maximal initial steroidogenic activity, persistent steroidogenesis is induced at all levels of the toxin. Steroidogenic responses are detectable with 10 pg/ml of choleragen or less. The respective effects of ACTH and choleragen on cyclic-AMP synthesis and release into the medium parallel those on steroidogenesis. Intracellular cyclic-AMP levels in ACTH-treated cells reach a peak within 20-30 minutes and decline to normal levels within 2-4 hours. In choleragen-treated cells, after the lage period, the levels of intracellular cyclic-AMP remain above control levels indefinitely. The effects of ACTH and choleragen on cyclic-AMP biosynthesis are additive at all levels of the two compounds. The effects of choleragen are blocked by prior treatment of the toxin with a five-fold molar excess of ganglioside GM1, a presumed constituent of the toxin-binding site.
Subsequent to previous observations suggesting a close association between the relaxing actions of PGI2 and its increasing effects on cyclic AMP levels in bovine coronary smooth muscle, evidence indicative of a transmitter function of cAMP in PGI2-induced relaxation is presented, by showing that a) in time course experiments in circular strips of bovine coronary arteries the increase in cAMP-levels caused by PGI2 preceded the mechanical response, b) the relaxant as well as cAMP-increasing effects produced by PGI2 were significantly potentiated by the PDE-inhibitor MIX, and c) in a particulate preparation of bovine coronary arteries PGI2 concentration dependently stimulated adenylate cyclase in the presence of GTP.
1. The inhibitory action of caffeine on catecholamine secretion induced by secretagogues was investigated in perfused adrenal glands and dispersed chromaffin cells of the guinea-pig. 2. Caffeine (10 mM) caused a reversible inhibition of catecholamine secretion evoked by acetylcholine (ACh, 50 microM), KCl (56 mM, high K+) and veratridine (100 microM) and that induced by muscarinic receptor activation in the absence of extracellular Ca2+ in perfused adrenal glands. 3. In dispersed chromaffin cells, caffeine caused a dose-dependent inhibition of the secretory responses to 100 microM ACh and veratridine. Forskolin (30 microM), dibutyryl cyclic AMP (1 mM) and 8-bromo cyclic AMP (1 mM) did not mimic the action of caffeine. 4. In the voltage-clamp, whole-cell recording mode (at a holding potential of -60 mV or -70 mV), ACh (100 microM) evoked an inward current, and depolarizing pulses elicited inward Na+, Ca2+ and outward K+ currents. All these responses were partially inhibited by caffeine (20 mM). 5. ACh rapidly increased the intracellular concentration of Ca2+ ([Ca2+]i) in fura-2-loaded cells in either the presence or the absence of external Ca2+, though its magnitude was decreased by about 50% in Ca(2+)-free conditions. Caffeine (20 mM) inhibited these ACh-induced increases in [Ca2+]i. 6. In permeabilized chromaffin cells, caffeine (20 mM) caused an inhibition of catecholamine secretion evoked by Ca2+ (10 microM). 7. These results suggest that caffeine inhibits evoked catecholamine secretion through mechanisms such as the blockade of voltage-dependent Na+ and Ca2+ currents and ACh receptor current, and reduction of the release of intracellularly stored Ca2+ and/or Ca(2+)-sensitivity of the secretory apparatus.
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The action of AD6 was tested in vitro on human platelets by measuring beta-thromboglobulin (BTG), platelet factor 4 (PF4) and thromboxane B2 (TXB2) release as well as aggregation. BTG and PF4 release from blood anticoagulated with sodium citrate was inhibited by AD6 during a 3 h incubation. Platelet rich plasma (PRP) was stimulated with ADP, collagen, sodium arachidonate, PAF, A23187 and epinephrine, while resuspended washed platelets (WP) were stimulated by thrombin. AD6 (5-100 microM) inhibited dose dependently aggregation, BTG, PF4 and TXB2 release induced by threshold concentration of all the tested aggregating agents; however AD6 action could be overcome by increasing the concentration of the stimulating agents. After cyclo-oxygenase blockade by acetylsalicylic acid (ASA), PRP was stimulated by a supramaximal concentration of PAF. Under these circumstances we could observe a reversible aggregation and a partial release of BTG and PF4, AD6 was able to further reduce aggregation and release. Cyclic AMP accumulation induced in WP by prostacyclin was not modified by AD6 (100 microM), while theophylline greatly potentiated prostacyclin action. We conclude that AD6 is an inhibitor of platelet activation in vitro. Its mode of action is different from cyclo-oxygenase blockade and provides inhibition of platelet activation by a number of different stimuli.
The in vitro effect of various diuretics on rat kidney adenylate cyclase was investigated in crude homogenates of the cortex, the outer and inner medulla. 10-3 M furosemide inhibited adenylate cyclase by 40% in the cortex, by 16% in the outer medulla and by 43% in the inner medulla. 10-3 M ethacrynic acid inhibited adenylate cyclase activity by 65% in the cortex, 59% in the outer medulla and by 57% in the inner medulla. Amiloride produced no significant inhibition of the adenylate cyclase reaction. In the cortex, furosemide partially inhibited adenylate cyclase under basal, fluoride-stimulated and parathyroid hormone-stimulated conditions. Ethacrynic acid produced a strong inhibition of adenylate cyclase activation by F- and parathyroid hormone. In the inner medulla 10-2 M F- and 1 mU antidiuretic hormone reversed the furosemide effect on adenylate cyclase. Ethacrynic acid produced a strong inhibition of adenylate cyclase in the presence of F- and antidiuretic hormone. It is suggested that inhibition of renal adenylate cyclase might be a possible mode of action of certain diuretics.
The discovery of disc protein renewal in rod outer segments, in 1960s, was followed by the observation that old discs were ingested by the retinal pigment epithelium. This process occurs in both rods and cones and is crucial for their survival. Photoreceptors completely degenerate in the Royal College of Surgeons mutant rat, whose pigment epithelium cannot ingest old discs. The complete renewal process includes the following sequential steps involving both photoreceptor and pigment epithelium activity: new disc assembly and old disc shedding by photoreceptor cells; recognition and binding to pigment epithelium membranes; then ingestion, digestion, and segregation of residual bodies in pigment epithelium cytoplasm. Regulating factors are involved at each step. While disc assembly is mostly genetically controlled, disc shedding and the subsequent pigment epithelium phagocytosis appear regulated by environmental factors (light and temperature). Disc shedding is rhythmically controlled by an eye intrinsic circadian oscillator using endogenous dopamine and melatonin as light and dark signal, respectively. Of special interest is the regulation of phagocytosis by multiple receptors, including specific phagocytosis receptors and receptors for neuroactive substances released from the neuroretina. The candidates for phagocytosis receptors are presented, but it is acknowledged that they are not completely known. The main neuromodulators are adenosine, dopamine, glutamate, serotonin, and melatonin. Although the transduction mechanisms are not fully understood, attention was brought to cyclic AMP, phosphoinositides, and calcium. The chapter points to the multiplicity of regulating factors and the complexity of their intermingling modes of action. Promising areas for future research still exist in this field.
The global increase in human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and sexually transmitted infections (STIs) has led to the introduction of barrier methods, such as condoms. However, drawbacks associated with condoms, such as men being reluctant to use them and women being unable to negotiate their use, have led to the search for better and acceptable alternatives, namely the microbicides. These are gel formulations that, when used prior to sexual intercourse, protect against the transmission of HIV and other STIs. However, after observing the side-effects of nonoxynol-9, a component of the microbicidal formulations available on the market, the focus has shifted to natural available compounds demonstrating the preferred protective effects. Antimicrobial peptides (AMPs) are one such group of compounds present in a wide range of organisms from bacteria to humans. The existing 750 or so, low-molecular-weight, cationic charged peptides are classified into five major groups based on their three-dimensional structure obtained by nuclear magnetic resonance studies. The hypothesized mode of action seems to be the interaction of the positively charged peptides with the negatively charged phospholipids present on the surface of the cell membrane. Various studies have demonstrated the effect of several AMPs, namely, defensins, protegrins, cathelicidins, cecropins, polyphemusins, magainins and melittins, against various STI-causing pathogens and HIV/herpes simplex virus, both in vitro and in vivo. The contraceptive efficacies of magainin and nisin in vitro and in vivo are worth mentioning. We believe these peptides are suitable candidates in the development of newer mechanism-based microbicides in future.