Abstract
Cultured neonatal sympathetic neurons can synthesize and corelease norepinephrine (NE) and acetylcholine (ACh). Evoked release of NE has an excitatory effect on the beat rate of cocultured cardiac myocytes while ACh release results in myocyte inhibition. Here we show that the cholinergic properties of the neurons and the relative level of NE and ACh corelease are modulated by neurotrophic factors. Brain-derived neurotrophic factor (BDNF) rapidly promoted ACh release in the absence of cholinergic differentiation activity and even in neurons that were predominantly noradrenergic. This increase in the cholinergic component of sympathetic cotransmission was sufficient for myocytes to display an overall inhibitory response to neuronal stimulation. In contrast, short-term growth in ciliary neurotrophic factor (CNTF) resulted in the upregulation of cholinergic and downregulation of noradrenergic markers without an effect on normal excitatory neurotransmission. Only once the cells had acquired a cholinergic phenotype did CNTF acutely promote the evoked release of the cholinergic vesicle pool. The results of this study indicate that BDNF and CNTF, acting through independent pathways, modulate NE and ACh cotransmission to regulate the level of sympathetic excitation or inhibition of cardiac myocytes.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcholine / metabolism*
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Animals
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Animals, Newborn
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Brain-Derived Neurotrophic Factor / metabolism*
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Brain-Derived Neurotrophic Factor / pharmacology
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cells, Cultured
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Choline O-Acetyltransferase / genetics
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Ciliary Neurotrophic Factor / metabolism*
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Ciliary Neurotrophic Factor / pharmacology
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Coculture Techniques
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Ganglia, Sympathetic / drug effects
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Ganglia, Sympathetic / growth & development
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Ganglia, Sympathetic / metabolism*
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Mice
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Mice, Knockout
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Neural Inhibition / drug effects
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Neural Inhibition / physiology
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Neurons / drug effects
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Neurons / metabolism*
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Norepinephrine / metabolism
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Norepinephrine Plasma Membrane Transport Proteins
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Phenotype
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RNA, Messenger / metabolism
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Rats
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Symporters / genetics
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Tyrosine 3-Monooxygenase / genetics
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Up-Regulation / drug effects
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Up-Regulation / physiology
Substances
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Brain-Derived Neurotrophic Factor
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Ciliary Neurotrophic Factor
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Norepinephrine Plasma Membrane Transport Proteins
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RNA, Messenger
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Slc6a2 protein, mouse
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Slc6a2 protein, rat
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Symporters
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Tyrosine 3-Monooxygenase
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Choline O-Acetyltransferase
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Acetylcholine
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Norepinephrine