Role for calcium/calmodulin-dependent protein kinase II in the p75-mediated regulation of sympathetic cholinergic transmission

Abstract

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. Calcium͞calmodulin-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 ␦-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.brain-derived neurotrophic factor ͉ p75 ͉ sympathetic neurons D eveloping and cultured sympathetic neurons can express both noradrenergic and cholinergic properties and are capable of coreleasing norepinephrine (NE) and acetylcholine (ACh) (1-6). Ultrastructural studies of these dual noradrenergic͞cholinergic neurons have identified morphologically distinct populations of vesicles (7-9), and localization of the vesicular monoamine transporters and vesicular acetylcholine transporter suggest that NE and ACh are stored in distinct vesicle pools, even within the same synaptic varicosity (10-15). ACh and NE are released from sympathetic neurons in an activity-dependent manner, and this release can be modulated by target-derived factors (16,17).Nerve growth factor (NGF) and brain-derived neurotrophic factors (BDNF) are two members of the neurotrophin family of neurotrophic factors that have distinct effects on sympathetic cholinergic and noradrenergic transmission. Neurotransmission between sympathetic neurons and cardiac myocytes can be measured in culture by monitoring the beat rate of spontaneously contracting cardiac myocytes during stimulation of a connected neuron (18). NGF promotes the activity-dependent release of NE from neonatal sympathetic neurons onto myocytes, resulting in an increase in the beat rate of the myocytes (16). In contrast, BDNF potentiates the activity-dependent release of ACh, resulting in the inhibition of myocyte beat rate (17). BDNF-induced cholinergic transmission takes place through a presynaptic mechanism and, because B...

Subtoxic N‐methyl‐D‐aspartate delayed neuronal death in ischemic brain injury through TrkB receptor‐ and calmodulin‐mediated PI‐3K/Akt pathway activation

“…W-13, a specific CaM inhibitor, could greatly block this effect. W-12, a control drug for W-13 (Perez-Garcia et al, 2004;Slonimsky et al, 2006), did not have this effect. These findings suggested that calmodulin acted at upstream of Akt pathway in the cell survival path- Immunohistochemistry assessment of phosphorylated Akt in the hippocampal CA1 region.…”

“…-binding protein (Chin and Means, 2000), regulates multiple processes in eukaryotic cells, including cytoskeletal organization and vesicular trafficking, in eukaryotic cells and plays important roles in regulating synaptic plasticity and mitogenesis (Baral et al, 2000;Shi and Ethell, 2006;Slonimsky et al, 2006). When bound to Ca 21 / calmodulin undergoes a conformational change that allows it to bind to target effector proteins and to stimulate or inhibit their activities.…”

Modulation of Ca V 2.1 channels by Ca 2+ /calmodulin-dependent protein kinase II bound to the C-terminal domain

“…Postsynaptic CaMKII activity is required for induction of long-term potentiation in the CA1 region of the hippocampus and for spatial learning and memory (25)(26)(27)(28); mutant animals lacking ␣CaMKII display impaired hippocampus-dependent learning (27,29,30). Compared with the well documented role of CaMKII in regulating the postsynaptic response, the potential role of CaMKII in regulating presynaptic function is unclear, although it has been shown to regulate neurotransmission (31)(32)(33)(34)(35) and to alter the specificity of neurotransmitter release (36). Here we report that CaMKII constitutively binds to the ␣ 1 2.1 subunit of Ca V 2.1 channels and modulates their inactivation properties in both transfected cells and hippocampal neurons.…”

Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties

“…As will be detailed below, neurotrophins rapidly influence neurotransmission in cultured sympathetic neurons in a manner that is differentially regulated through different neurotrophin receptors (Lockhart et al, 1997; Yang et al, 2002; Slonimsky et al, 2003; Slonimsky et al, 2006). Therefore it will be helpful to briefly review neurotrophin receptor expression in sympathetic neurons, for a more detailed treatment see (Chao and Hempstead, 1995; Chao, 2003; Reichardt, 2006).…”