Analysis of the Structure and Electrophysiological Actions of Halitoxins: 1,3 Alkyl-pyridinium Salts from Callyspongia ridleyi |
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Authors: | RH Scott AD Whyment A Foster KH Gordon BF Milne M Jaspars |
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Institution: | (1) Department of Biomedical Sciences, Institute of Medical Sciences, Aberdeen University, Foresterhill, Aberdeen AB25 2ZD, UK, GB;(2) Marine Natural Products Laboratory, Department of Chemistry, University of Aberdeen, Old Aberdeen, AB24 3UE, UK, GB |
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Abstract: | We have chemically characterized a preparation of halitoxins, (1,3 alkyl-pyridinium salts) isolated from the marine sponge
Callyspongia ridleyi. At concentrations of 50 and 5 μg/ml the halitoxin preparation caused irreversible membrane potential depolarization, decreased
input resistance and inhibited evoked action potentials when applied to cultured dorsal root ganglion neurones. Under whole
cell voltage clamp the halitoxins produced an increase in cation conductance that was attenuated by replacing sodium with
N-methyl-d-glucamine. Fura-2 fluorescence ratiometric calcium imaging was used to directly measure calcium flux into neurones after
exposure to halitoxins. Calcium influx, evoked by the halitoxins, persisted when the neurones were bathed in medium containing
the voltage-activated calcium channel antagonists cadmium and nickel. Experiments on undifferentiated F-11 cells showed little
or no calcium influx in response to depolarizing concentrations of potassium and indicated that halitoxins evoked massive
calcium influx in the absence of voltage-activated calcium channels. The halitoxins also produced transient increases in intracellular
calcium when F-11 cells were bathed in calcium-free medium suggesting that the toxins could release calcium from intracellular
stores. The pore-forming action of the halitoxins was identified when the toxins were applied to artificial lipid bilayers
composed of phosphatidylcholine and cholesterol. Halitoxins evoked channel-like activity in the lipid bilayers, with estimated
unitary conductances of between 145pS and 2280pS, possibly indicating that distinct channels could be produced by the different
components in the preparation of halitoxins.
Received: 23 December 1999/Revised: 3 April 2000 |
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Keywords: | : Calcium permeant ion channel — Pore former — Halitoxin — Sensory neurone — Lipid bilayer |
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