Biological Applications and Evolutionary Origins of Ionophores

Pressman, Berton C.; deGuzman, Norberto T.

doi:10.1007/978-1-4684-3279-4_14

Cited by 10 publications

(10 citation statements)

References 16 publications

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“…Exposure to A23187 results in increased 4:'Ca release and cAMP production in cultured fetal rat forelimb rudiments [4 7], and incubation of isolated fetal rat calvarial cells with A23187 produces a rapid calcium influx associated with increased cAMP content [4,5]. A23187-stimulated increases in intracellular calcium concentration have been shown to be associated with production of hormone-like effects in a variety of tissues [8][9][10]. PTH and A23187 both stimulate initial calcium influx in bone cells [1,2,111.…”

Section: Discussionmentioning

confidence: 99%

Comparison of parathyroid hormone and calcium ionophore A23187 effects on bone resorption and nucleic acid synthesis in cultured fetal rat bone

et al. 1982

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It has recently been demonstrated that calcium ionophore A23187 mimics certain of the effects of parathyroid hormone (PTH) on bone in vitro, including stimulation of 45Ca release and cAMP formation. To further examine the relative effects of these two agents on bone cell metabolism, we compared the effects of synthetic PTH 1-34 (50 ng/ml) and calcium ionophore A23187 (0.5 micrograms/ml) on 45Ca release, DNA concentration, and nucleic acid synthesis in fetal rat forelimb rudiments cultured for periods up to 120 h. Both agents stimulated 45Ca release; however, the effects of PTH were apparent after a shorter period of exposure. Bone DNA concentration (expressed as microgram DNA/mg bone) was not affected by PTH but was significantly increased relative to control values by exposure to A23187 for 8-120 h of incubation. PTH increased the incorporation of 3H-thymidine into DNA at 30 and 48 h, and increased the incorporation of 14C-uridine into RNA at 48 h, time points which corresponded to a period of accelerated PTH stimulation of 45Ca release. In contrast, 3H-thymidine and 14C-uridine incorporation were both uniformly suppressed by A23187 at all time points examined. Thus the increased DNA concentration observed in A23187-treated rudiments appeared to be the result of a decreased rate of bone maturation and mineralization. The markedly different patterns of nucleic acid synthesis in response to PTH and A23187 suggest that these agents differ significantly in their mechanisms of action on bone cell metabolism.

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Section: Discussionmentioning

confidence: 99%

Comparison of parathyroid hormone and calcium ionophore A23187 effects on bone resorption and nucleic acid synthesis in cultured fetal rat bone

et al. 1982

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“…In barbiturated dogs, at dosage 2 mg/kg, it caused a threefold increase in the contractility as well as a modest rise in aortic pressure and heart rate. It also induced a drop in total peripheral resistance followed by a drastic increase in blood flow through the coronary arteries of the left ventricle [3]. The exact MOA through which these carboxyl polyethers induce contractility of cardiac muscle is still unclear.…”

Section: Cardiovascular Effectsmentioning

confidence: 99%

“…First used in 1967, the term ionophore refers to the molecule's ability to bind a metal ion and facilitate its transport across cellular membranes. This chemo-physiological property has made polyether ionophores a useful tool in the study of cation transport mechanisms and has been the rationalization for their biological activities [1,3].…”

Section: Introductionmentioning

confidence: 99%

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Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites

Kevin¹,

Meujo

Hamann³

2009

Expert Opinion on Drug Discovery

166

137

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Background As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics.

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“…One of the original interests in ionophores was their percewed potential for directly modifying intracellular iomc gradients, pamcularly Ca 2+, winch would lead, hopefully, to the development of useful pharmacologic agents or, alternatively, provide a tool for studying cellular functtons medmted by changes m Ca 2+ [13,14]. Of parttcular interest were divalent xonophores such as X-537A (normally considered a Ca 2+ ionophore -note, however, X-537A complexes Na ÷ and K + almost as well as Ca 2+) winch have been shown to mduce contractaon of aortic strips and increase the rate of contractility of tsolated perfused rabbit heart [5,15], and release Ca 2+ from energy-loaded vesicles derived from the sarcoplasrmc renculum of muscle [16][17][18] X-537A may also mcrease blood flow through coronary artenes and mcrease cardiac output [19].…”

Section: Mode Of Actionmentioning

confidence: 99%

Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity

Mollenhauer

Morré

Rowe

1990

Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes

578

411

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Monensin, a monovalent ion-selective ionophore, facilitates the transmembrane exchange of principally sodium ions for protons. The outer surface of the ionophore-ion complex is composed largely of nonpolar hydrocarbon, which imparts a high solubility to the complexes in nonpolar solvents. In biological systems, these complexes are freely soluble in the lipid components of membranes and, presumably, diffuse or shuttle through the membranes from one aqueous membrane interface to the other. The net effect for monensin is a trans-membrane exchange of sodium ions for protons. However, the interaction of an ionophore with biological membranes, and its ionophoric expression, is highly dependent on the biochemical configuration of the membrane itself. One apparent consequence of this exchange is the neutralization of acidic intracellular compartments such as the trans Golgi apparatus cisternae and associated elements, lysosomes, and certain endosomes. This is accompanied by a disruption of trans Golgi apparatus cisternae and of lysosome and acidic endosome function. At the same time, Golgi apparatus cisternae appear to swell, presumably due to osmotic uptake of water resulting from the inward movement of ions. Monensin effects on Golgi apparatus are observed in cells from a wide range of plant and animal species. The action of monensin is most often exerted on the trans half of the stacked cisternae, often near the point of exit of secretory vesicles at the trans face of the stacked cisternae, or, especially at low monensin concentrations or short exposure times, near the middle of the stacked cisternae. The effects of monensin are quite rapid in both animal and plant cells; i.e., changes in Golgi apparatus may be observed after only 2-5 min of exposure. It is implicit in these observations that the uptake of osmotically active cations is accompanied by a concomitant efflux of H+ and that a net influx of protons would be required to sustain the ionic exchange long enough to account for the swelling of cisternae observed in electron micrographs. In the Golgi apparatus, late processing events such as terminal glycosylation and proteolytic cleavages are most susceptible to inhibition by monensin. Yet, many incompletely processed molecules may still be secreted via yet poorly understood mechanisms that appear to bypass the Golgi apparatus. In endocytosis, monensin does not prevent internalization. However, intracellular degradation of internalized ligands may be prevented.(ABSTRACT TRUNCATED AT 400 WORDS)

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Biological Applications and Evolutionary Origins of Ionophores

Cited by 10 publications

References 16 publications

Comparison of parathyroid hormone and calcium ionophore A23187 effects on bone resorption and nucleic acid synthesis in cultured fetal rat bone

Comparison of parathyroid hormone and calcium ionophore A23187 effects on bone resorption and nucleic acid synthesis in cultured fetal rat bone

Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites

Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity

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