Abstract
While nicotine is known to act at neuronal nicotinic acetylcholine receptors (nAChRs) to facilitate neurotransmitter release, the mechanisms underlying this action are poorly understood. Some of its effects are known to be mediated by presynaptic receptors. In the mouse vas deferens nicotine (10-30 microM) transiently increased the force of neurogenic contraction by 135+/-25%, increased the amplitude of excitatory junction potentials by 74+/-6% and increased the frequency of spontaneous excitatory junction potentials in four out of six preparations. Confocal microscopy and the calcium indicator Oregon Green 488 BAPTA-1 dextran were used to measure calcium concentration changes in the nerve terminals. Nicotine did not affect the action potential-evoked calcium transient but instead triggered small, random fluctuations ("calcium spikes") in intra-varicosity calcium concentrations at an average frequency of 0.09+/-0.02 Hz. These were insensitive to tetrodotoxin at a concentration that blocked action-potential evoked calcium transients (300 nM). They were abolished by the nAChR blocker hexamethonium (100 microM) and by both ryanodine (100 microM) and caffeine (3 mM), agents that modify calcium release from intracellular stores. We propose a novel mechanism whereby nicotine's action at nAChRs triggers calcium-induced calcium release from a ryanodine-sensitive calcium store in nerve terminals. This primes neurotransmitter release mechanisms and enhances both spontaneous and action potential-evoked neurotransmitter release.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-Antagonists / pharmacology
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Animals
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Caffeine / pharmacology
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Calcium / metabolism*
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Calcium Channels / drug effects
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Calcium Channels / metabolism
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Calcium Signaling / drug effects*
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Calcium Signaling / physiology
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Electric Stimulation
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Fluorescent Dyes / pharmacokinetics
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Hexamethonium / pharmacology
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Intracellular Fluid / drug effects*
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Intracellular Fluid / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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Muscle Contraction / drug effects
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Muscle Contraction / physiology
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Muscle, Smooth / drug effects
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Muscle, Smooth / innervation
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Muscle, Smooth / physiology
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Neuromuscular Junction / drug effects*
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Neuromuscular Junction / metabolism
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Neuromuscular Junction / ultrastructure
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Nicotine / pharmacology*
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Nicotinic Antagonists / pharmacology
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Organic Chemicals
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Prazosin / pharmacology
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Presynaptic Terminals / drug effects*
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Presynaptic Terminals / metabolism
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Presynaptic Terminals / ultrastructure
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Receptors, Nicotinic / drug effects*
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Receptors, Nicotinic / metabolism
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Ryanodine / pharmacology
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Sympathetic Fibers, Postganglionic / cytology
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Sympathetic Fibers, Postganglionic / drug effects
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Sympathetic Fibers, Postganglionic / metabolism
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Tetrodotoxin / pharmacology
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Vas Deferens / drug effects
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Vas Deferens / innervation
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Vas Deferens / physiology
Substances
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Adrenergic alpha-Antagonists
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Calcium Channels
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Fluorescent Dyes
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Nicotinic Antagonists
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Oregon Green BAPTA-dextran
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Organic Chemicals
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Receptors, Nicotinic
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Ryanodine
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Hexamethonium
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Caffeine
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Tetrodotoxin
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Nicotine
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Calcium
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Prazosin