Abstract
dc:description.abstractCalcium (Ca2+) is a main secondary messenger in nearly all eukaryotic cells, including those belonging to the central and peripheral nerve system. Free intracellular Ca2+ ([Ca2+]i) in resting cells is maintained at low concentrations (submicromolar range). In contrast, the Ca2+ concentration in the extracellular space and the endoplasmic lumen exceeds the 103 - 106 range. This results in a cytosolic - directed Ca2+ flow whenever a Ca2+ permeable ion channel opens on the plasma or endoplasmic membrane. These Ca2+ flows are often triggered by extracellular ligands like neurotropic factors (brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF)), neurotransmitters (glutamate, NMDA) or even adenosine 5’ - triphosphate (ATP). In some cases, a Ca2+ elevation occurs without apparent stimulation and are therefore denoted as ’spontaneous’ Ca2+ elevations. My doctoral work is focused on the regulation of cytosolic Ca2+ in cells belonging to the nerve system, with a particular interest in microglia, the immune cells of the nerve system. Like all other cells, microglia cells possess many receptors and Ca2+ channels in the plasma membrane, including receptors for classical neurotransmitters. Experiments in living animals revealed that microglia can display spontaneous cytosolic Ca2+ elevations. It was, however, unclear if these elevations were triggered by released neurotransmitters, extracellular ligands, intracellular or autocrine signalling. Therefore I performed Ca2+ imaging experiments with cultured microglia and detected spontaneous Ca2+ elevations in 50% of the isolated microglia cells in absence of neurons and other glial cells. Sequential experiments indicated that these elevations are regulated via phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3) and inositol 1,4,5-trisphosphate receptor (IP3R) on the endoplasmic membrane. Purinergic signalling was excluded as autocrine trigger of these events. In a second study, I showed that cultivated microglia lack functional NMDA receptors on the plasma membrane. In contrast to the in situ patch clamp experiments of S. Wendt, where NMDA triggered a plasma membrane current, a Ca2+ elevation after NMDA application remained absent in vitro. In the peripheral system, increased expression of neurotropic factors (ciliary neurotrophic factor (CNTF), BDNF, GDNF, vascular endothelial growth factor (VEGF), neurotrophin - 3 (NT - 3) and nerve growth factor (NGF)) could lead to an increased internal Ca2+ concentration due to the continuous stimulation of the PLC dependent signalling pathway(s). I investigated if long - term elevated Ca2+ concentration (20 weeks) could change proliferation and regeneration of nerve cells after damage. However, neurotropic factor overexpression did not improve motor or sensory recovery after sciatic nerve injury in rats.
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Korvers, Laura
Subjects
dc:subject × 5Rights
- Licence dc:rights.uri
- Language dc:language
- eng
Identifiers
dc:identifier.*- Identifier URI
- http://dx.doi.org/10.17169/refubium-18093