Abstract
Most people with diabetes develop severe complications of the autonomic nervous system; yet, the underlying causes of many diabetic-induced dysautonomias are poorly understood. Here we explore the idea that these dysautonomias results, in part, from a defect in synaptic transmission. To test this idea, we investigated cultured sympathetic neurons and show that hyperglycemia inactivates nAChRs through a mechanism involving an elevation in reactive oxygen species and an interaction with highly conserved cysteine residues located near the intracellular mouth of the nAChR channel. Consistent with this, we show that diabetic mice have depressed ganglionic transmission and reduced sympathetic reflexes, whereas diabetic mice expressing mutant postsynaptic nAChRs that lack the conserved cysteine residues on the alpha3 subunit have normal synaptic transmission in sympathetic ganglia and normal sympathetic reflexes. Our work suggests a new model for diabetic-induced dysautonomias and identifies ganglionic nAChRs as targets of hyperglycemia-induced downstream signals.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / pharmacology
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Adenoviridae
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Age Factors
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Aldehydes / metabolism
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Animals
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Animals, Newborn
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Body Temperature / drug effects
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Body Temperature / physiology
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Cells, Cultured
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Cysteine / genetics
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Cysteine / metabolism*
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Diabetes Mellitus, Experimental / chemically induced
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Diabetes Mellitus, Experimental / pathology*
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Glucose / pharmacology
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Guanidines / pharmacology
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Heart Rate / drug effects
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Heart Rate / physiology
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Hypoglycemic Agents / pharmacology
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Insulin / pharmacology
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Leptin / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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Oxidative Stress / drug effects
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Oxidative Stress / physiology
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Patch-Clamp Techniques
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Reactive Oxygen Species / metabolism
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Receptors, Leptin / genetics
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Receptors, Nicotinic / deficiency
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Receptors, Nicotinic / metabolism*
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Sensory Receptor Cells / physiology*
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Superior Cervical Ganglion / pathology*
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology*
Substances
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Aldehydes
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Enzyme Inhibitors
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Guanidines
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Hypoglycemic Agents
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Insulin
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Leptin
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Reactive Oxygen Species
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Receptors, Leptin
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Receptors, Nicotinic
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nicotinic receptor subunit alpha3
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Glucose
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4-hydroxy-2-nonenal
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Cysteine
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Acetylcholine
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pimagedine