Block of P/Q-Type Calcium Channels by Therapeutic Concentrations of Aminoglycoside Antibiotics

Pichler, Maria; Wang, Zhengyi; Grabner-Weiss, Christina; Reimer, Daniel; Hering, Steffen; Grabner, Manfred; Glossmann, Hartmut; Striessnig, Jörg

doi:10.1021/bi961657t

Cited by 51 publications

(36 citation statements)

References 32 publications

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“…We therefore also subjected 125 I--CTx-GVIA-and 125 I--CTx-MVIIC-labeled channel complexes extracted from cerebral cortex and cerebellum to immunoprecipitation with our antibodies. We have previously shown that under our experimental conditions saturable high affinity 125 I--CTx-GVIA and 125 I--CTx-MVIIC binding occurs selectively to N-type and P/Q-type Ca 2ϩ channels, respectively, with dissociation constants in the subpicomolar range (31).…”

Section: Similar ␤ Subunit Composition Of L- N- and P/q-type Ca 2ϩmentioning

confidence: 70%

β Subunit Heterogeneity in Neuronal L-type Ca2+Channels

Pichler

Cassidy

Reimer

et al. 1997

Journal of Biological Chemistry

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106

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Heterologous expression studies have shown that the activity of voltage-gated Ca 2؉ channels is regulated by their ␤ subunits in a ␤ subunit isoform-specific manner. In this study we therefore investigated if one or several ␤ subunit isoforms associate with L-type Ca 2؉ channels in different regions of mammalian brain.All four ␤ subunit isoforms (␤1b, ␤2, ␤3, and ␤4) are expressed in cerebral cortex as shown in immunoblots. Immunoprecipitation of (؉)-[3 H]isradipine-labeled Ltype channels revealed that the majority of ␤ subunitassociated L-type channels was associated with ␤3 (42 ؎ 8%) and ␤4 (42 ؎ 7%) subunits, whereas ␤1b and ␤2 were present in a smaller fraction of channel complexes. ␤3 and ␤4 were also the major L-type channel ␤ subunits in hippocampus. In cerebellum ␤1b, ␤2, and ␤3 but not ␤4 subunits were expressed at lower levels than in cortex. Accordingly, ␤4 was the most prominent ␤ subunit in cerebellar L-type channels. This ␤ subunit composition was very similar to the one determined for 125 I--conotoxin-GVIA-labeled N-type and 125 I--conotoxin-MVIIClabeled P/Q-type channel complexes in cerebral cortex and cerebellum.Our data show that all four ␤ subunit isoforms associate with L-type Ca 2؉ channels in mammalian brain. This ␤ subunit heterogeneity may play an important role for the fine tuning of L-type channel function and modulation in neurons.Voltage-gated Ca 2ϩ channels control the depolarization-induced influx of extracellular Ca 2ϩ into neurons and other electrically excitable cells. They exist as hetero-oligomeric complexes of different subunits (␣1, ␣2-␦, and ␤). Different types of neuronal Ca 2ϩ channels (termed L-, N-, P-, Q-, and R-type; 1) are discriminated by biophysical and pharmacological criteria (for reviews see Refs. 2-5). N-and P/Q-type channels are blocked by peptide toxins (-CTx

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Section: Similar ␤ Subunit Composition Of L- N- and P/q-type Ca 2ϩmentioning

confidence: 70%

β Subunit Heterogeneity in Neuronal L-type Ca2+Channels

Pichler

Cassidy

Reimer

et al. 1997

Journal of Biological Chemistry

Self Cite

106

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“…Benzalkonium chloride completely displaced radioligand binding to Nand P/Q-type VDCCs at 10 µM concentration and displayed a biphasic effect on the specific binding of [ 3 H]nitrendipine, with a very significant increase in binding when the concentration of benzalkonium chloride is as described to occur in numerous topical ocular preparations (≥200 µM or approximately 0.007%). The ability of benzalkonium chloride to interact with VDDCs is probably due to its quaternary ammonium structure: drugs sharing this structure, for example aminoglycoside antibiotics [20,41], are known to interact with VDDCs. Corneal epithelial cells may express L-type VDDCs [50] and hence an interaction of topical benzalkonium chloride with these channels could affect the physiology of the corneal surface.…”

Section: Discussionmentioning

confidence: 99%

Comparative effects of antiglaucoma drugs on voltage-dependent calcium channels

Melena

Stanton

Osborne

2001

Graefe's Arch Clin Exp Ophthalmol

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“…The underlying mechanism was later confirmed as a block of calcium channels, and aminoglycoside antibiotics were used as experimental tools to elucidate calcium channel function [Corrado et al, 1989]. Aminoglycosides may block N-type and P/Q-type channels in neurons [Pichler et al, 1996].…”

Section: Acute Side Effectsmentioning

confidence: 99%

Aminoglycoside Antibiotics

Forge

Schacht²

2000

Audiol Neurotol

595

504

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In the 50 years since their discovery, the aminoglycoside antibiotics have seen unprecedented use. Discovered in the 1940s, they were the long-sought remedy for tuberculosis and other serious bacterial infections. The side effects of renal and auditory toxicity, however, led to a decline of their use in most countries in the 1970s and 1980s. Nevertheless, today the aminoglycosides are still the most commonly used antibiotics worldwide thanks to the combination of their high efficacy with low cost. This review first summarizes the history, chemistry, antibacterial actions and acute side effects of the drugs. It then details the pathophysiology of aminoglycoside ototoxicity including experimental and clinical observations, risk factors and incidence. Pharmacokinetics, cellular actions and our current understanding of the underlying molecular mechanisms of ototoxicity are discussed at length. The review concludes with recent advances towards therapeutic intervention to prevent aminoglycoside ototoxicity.

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Block of P/Q-Type Calcium Channels by Therapeutic Concentrations of Aminoglycoside Antibiotics

Cited by 51 publications

References 32 publications

β Subunit Heterogeneity in Neuronal L-type Ca2+Channels

β Subunit Heterogeneity in Neuronal L-type Ca2+Channels

Comparative effects of antiglaucoma drugs on voltage-dependent calcium channels

Aminoglycoside Antibiotics

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