Subcellular Localization of Chromogranins, Calcium ChanneAmine Carriers, and Proteins of the Exocytotic Machinery in Bovine Splenic Nerve

Leitner, Bernd; Lovisetti-Scamihorn, Paola; Heilmann, Jutta; Striessnig, Jörg; Blakely, Randy D.; Eiden, Lee E.; Winkler, Hans

doi:10.1046/j.1471-4159.1999.0721110.x

Cited by 37 publications

(9 citation statements)

References 51 publications

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“…Despite a previous hypothesis (Kippenberger et al, 1999; Schroeter et al, 2000; Savchenko et al, 2003), neuronal NET does not appear to sort to dense core vesicles (Leitner et al, 1999; Matthies et al, 2009) nor to several other presynaptic membrane compartments (Matthies et al, 2009). Thus, endocytic compartments are a reasonable candidate.…”

Section: Introductionmentioning

confidence: 56%

“…A substantial portion of NET resides in intracellular vesicles of unknown nature (Leitner et al, 1999; Schroeter et al, 2000; Miner et al, 2003; Miner et al, 2006). Despite a previous hypothesis (Kippenberger et al, 1999; Schroeter et al, 2000; Savchenko et al, 2003), neuronal NET does not appear to sort to dense core vesicles (Leitner et al, 1999; Matthies et al, 2009) nor to several other presynaptic membrane compartments (Matthies et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Rab11 Supports Amphetamine-Stimulated Norepinephrine Transporter Trafficking

Matthies

Moore²,

Saunders³

et al. 2010

Journal of Neuroscience

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The norepinephrine transporter (NET) is a presynaptic plasma membrane protein that mediates reuptake of synaptically released norepinephrine. NET is also a major target for medications used for the treatment of depression, attention deficit/hyperactivity disorder, narcolepsy, and obesity. NET is regulated by numerous mechanisms, including catalytic activation and membrane trafficking. Amphetamine (AMPH), a psychostimulant and NET substrate, has also been shown to induce NET trafficking. However, neither the molecular basis nor the nature of the relevant membrane compartments of AMPH-modulated NET trafficking has been defined. Indeed, direct visualization of drug-modulated NET trafficking in neurons has yet to be demonstrated. In this study, we used a recently developed NET antibody and the presence of large presynaptic boutons in sympathetic neurons to examine basal and AMPH-modulated NET trafficking. Specifically, we establish a role for Rab11 in AMPHinduced NET trafficking. First, we found that, in cortical slices, AMPH induces a reduction in surface NET. Next, we observed AMPH-induced accumulation and colocalization of NET with Rab11a and Rab4 in presynaptic boutons of cultured neurons. Using tagged proteins, we demonstrated that NET and a truncated Rab11 effector (FIP2⌬C2) do not redistribute in synchrony, whereas NET and wild-type Rab11a do. Analysis of various Rab11a/b mutants further demonstrates that Rab11 regulates NET trafficking. Expression of the truncated Rab11a effector (FIP2⌬C2) attenuates endogenous Rab11 function and prevented AMPH-induced NET internalization as does GDP-locked Rab4 S22N. Our data demonstrate that AMPH leads to an increase of NET in endosomes of single boutons and varicosities in a Rab11-dependent manner.

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Section: Introductionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Rab11 Supports Amphetamine-Stimulated Norepinephrine Transporter Trafficking

Matthies

Moore²,

Saunders³

et al. 2010

Journal of Neuroscience

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“…Ca 2+ regulation may involve many different steps of NET trafficking including translocation between intracellular vesicles, as well as insertion into and retrieval from the plasma membrane. NET is known to be present in multiple intracellular compartments, including LDCV, rab4-positive early endosomes, and rab11-positive recycling endosomes (Kippenberger, 1999; Leitner, 1999; Matthies et al , 2009; Matthies et al , 2010). NET and NET T30A may have different sensitivity to Ca 2+ mobilization from intracellular Ca 2+ stores due to differences in trafficking between these intracellular compartments.…”

Section: Discussionmentioning

confidence: 99%

“…Transporter trafficking appears to involve diverse cellular compartments. NET is found associated with noradrenaline-containing secretory granules/large dense core vesicles (LDCV) in PC12 cells (Kippenberger AG, 1999) and also found in early or recycling endosomes in sympathetic neurons and the cortex of brains (Leitner, 1999; Matthies et al , 2009; Matthies et al , 2010). …”

Section: Introductionmentioning

confidence: 99%

Ca 2+ dependent surface trafficking of norepinephrine transporters depends on threonine 30 and Ca 2+ calmodulin kinases

Sung

Binda

Savchenko

et al. 2017

Journal of Chemical Neuroanatomy

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The antidepressant-sensitive norepinephrine (NE) transporter (NET) inactivates NE released during central and peripheral neuronal activity by transport into presynaptic cells. Altered NE clearance due to dysfunction of NET has been associated with the development of mental illness and cardiovascular diseases. NET activity in vivo is influenced by stress, neuronal activity, hormones and drugs. We investigated the mechanisms of Ca2+ regulation of NET and found that Ca2+ influenced both Vmax and Km for NE transport into cortical synaptosomes. Changes in extracellular Ca2+ triggered rapid and bidirectional surface trafficking of NET expressed in cultured cells. Deletion of residues 28–47 in the NET NH2-terminus abolished the Ca2+ effect on surface trafficking. Mutagenesis studies identified Thr30 in this region as the essential residue for both Ca2+- dependent phosphorylation and trafficking of NET. Depolarization of excitable cells increased surface NET in a Thr30 dependent manner. A proteomic analysis, RNA interference, and pharmacological inhibition supported roles of CaMKI and CaMKII in Ca2+-modulated NE transport and NET trafficking. Depolarization of primary noradrenergic neurons in culture with elevated K+ increased NET surface expression in a process that required external Ca2+ and depended on CaMK activity. Hippocampal NE clearance in vivo was also stimulated by depolarization, and inhibitors of CaMK signaling prevented this stimulation. In summary, Ca2+ signaling influenced surface trafficking of NET through a CaMK-dependent mechanism requiring Thr30.

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“…The intracellular distribution of NESP55 differs among different tissues. In the adrenal medulla (Ischia et al,1997) and the splenic nerve (Leitner et al,1999), NESP55 was found in large dense‐core vesicles. However, NESP55 was also present in the slightly lighter vesicles in mouse corticotropic AtT‐20 cells and was secreted constitutively from these cells (Eder et al,2004).…”

mentioning

confidence: 99%

Neuroendocrine secretory protein 55 (NESP55) in the spinal cord of rat: An immunocytochemical study

Fischer‐Colbrie

Dahlström

2007

J of Comparative Neurology

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The immunohistochemical expression of a novel chromogranin-like protein, neuroendocrine secretory protein 55 (NESP55), in the rat spinal cord was investigated. NESP55-immunoreactive cells were detected in the ventral horn, intermediate laminae, and deep dorsal horn, comprising motoneurons, autonomic neurons, and interneurons throughout all spinal segments. Within laminae I-II of the dorsal horn, one or two NESP55-positive cells were often seen. Nerve fibers also contained NESP55 immunoreactivity (IR) and were particularly prominent in the ventral horn. No nerve terminals/varicosities appeared to contain NESP55 in any spinal lamina. Double-staining experiments revealed that a high proportion of the NESP55-positive neurons were cholinergic. Moreover, NESP55-IR in the motoneurons was evenly distributed in the whole cytoplasm with a finely granular appearance. In contrast, the fluorescent material in the preganglionic neurons was concentrated in the perinuclear region and largely overlapped with the trans-Golgi network marker TGN38. Our data provide detailed morphological information on the distribution of NESP55-IR in the rat spinal cord. Also, the differential intracellular expression of NESP55-IR in the spinal motoneurons and autonomic neurons suggests that NESP55 may be processed into different secretory granules and may be involved in both constitutive and regulated pathways in these neurons.

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Subcellular Localization of Chromogranins, Calcium ChanneAmine Carriers, and Proteins of the Exocytotic Machinery in Bovine Splenic Nerve

Cited by 37 publications

References 51 publications

Rab11 Supports Amphetamine-Stimulated Norepinephrine Transporter Trafficking

Rab11 Supports Amphetamine-Stimulated Norepinephrine Transporter Trafficking

Ca 2+ dependent surface trafficking of norepinephrine transporters depends on threonine 30 and Ca 2+ calmodulin kinases

Neuroendocrine secretory protein 55 (NESP55) in the spinal cord of rat: An immunocytochemical study

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