Role for calcium/calmodulin-dependent protein kinase II in the p75-mediated regulation of sympathetic cholinergic transmission.
Neurotrophins regulate sympathetic neuron cotransmission by modulating the activity-dependent release of norepinephrine and acetylcholine. Nerve growth factor promotes excitatory noradrenergic transmission, whereas brain-derived neurotrophic factor (BDNF), acting through the p75 receptor, increases inhibitory cholinergic transmission. This regulation of corelease by target-derived factors leads to the functional modulation of myocyte beat rate in neuron-myocyte cocultures. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the control of both pre- and postsynaptic mechanisms of synaptic plasticity. We demonstrate that CaMKII acts in conjunction with p75 signaling to regulate cholinergic transmission between sympathetic neurons and heart cells. Inhibition of presynaptic CaMKII prevents the BDNF-dependent shift to inhibitory neurotransmission, whereas presynaptic expression of a constitutively active CaMKII results in inhibitory neurotransmission in the absence of added BDNF, suggesting that activation of presynaptic CaMKII is both necessary and sufficient for a shift from excitatory to inhibitory transmission. Several isozymes of CaMKII are expressed in sympathetic neurons, with the delta-CaMKII being activated by BDNF and nerve growth factor. Activated CaMKII is less effective at promoting cholinergic transmission in the absence of p75 signaling, demonstrating that p75 and CaMKII act to coordinate neurotransmitter selection in sympathetic neurons.
Department of Biology, National Center for Behavior Genomics, Brandeis University, M/S 008, 415 South Street, Waltham, MA 02454, USA.
John D
JD
Slonimsky
Mark D
MD
Mattaliano
Jung-Il
JI
Moon
Leslie C
LC
Griffith
Susan J
SJ
Birren
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000819:agonists / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases