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Presynaptic phosphoprotein B-50/GAP-43 in neuronal and synaptic plasticity
J E Biewenga1, L H Schrama, W H Gispen
1Rudolf Magnus Institute for Neurosciences, Laboratory of Physiological Chemistry, Utrecht, The Netherlands.
Insights
Growth-associated protein B-50/GAP-43 is crucial for neuronal development and plasticity. Its phosphorylation state regulates neurotransmitter release and membrane expansion, impacting neuronal pathfinding and synaptic function.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- B-50/GAP-43 is a growth-associated phosphoprotein found in neuronal growth cones and presynaptic terminals.
- Its expression is highest in the developing nervous system and in adult brain regions with high plasticity.
Purpose of the Study:
- To investigate the role of B-50/GAP-43 in neuronal plasticity, neurite outgrowth, and transmitter release.
- To understand the regulatory mechanisms and interactions of B-50/GAP-43.
Main Methods:
- Analysis of B-50/GAP-43 gene expression and promoter activity.
- Studies on the effects of B-50/GAP-43 expression in non-neuronal cells.
- Investigation of post-translational modifications and protein interactions.
- Examination of B-50/GAP-43 phosphorylation during long-term potentiation in hippocampal slices.
Main Results:
- B-50/GAP-43 expression in non-neuronal cells promotes filopodial extensions.
- Antibodies or antisense oligonucleotides against B-50/GAP-43 inhibit neurite outgrowth.
- B-50/GAP-43 undergoes various post-translational modifications including phosphorylation and dephosphorylation.
- Increased B-50/GAP-43 phosphorylation during long-term potentiation enhances calmodulin binding and transmitter release.
Conclusions:
- B-50/GAP-43 is essential for neuronal pathfinding and neurite outgrowth.
- The phosphorylation state of B-50/GAP-43 modulates transmitter release by regulating calmodulin.
- B-50/GAP-43 plays a critical role in membrane expansion, linking neurite outgrowth and synaptic plasticity.
Abstract:
B-50/GAP-43 is a growth-associated phosphoprotein enriched in growth cones and in the presynaptic terminal. The expression of the protein is restricted to the nervous system and is highest in the first week after birth. In adult brain, B-50 is enriched in areas with high plasticity. The regulation of expression of the B-50 gene occurs both at the transcriptional and post-transcriptional level by unknown mechanisms. The gene contains 2 regions displaying promoter activity, the most 3' of which (P2) is the active on in vivo. Expression of B-50 in non-neuronal cells results in filopodial extensions whereas antibodies or antisense oligo's to B-50 prevent neurite outgrowth. The protein is important for neuronal pathfinding. Several post-translational modifications have been described, ADP-ribosylation and palmitoylation in the membrane binding domain, phosphorylation by PKC, casein kinase II and phosphorylase kinase, and dephosphorylation by several phosphatases, among which is calcineurin. Interactions of B-50 have been described with calmodulin, PIP kinase, F-actin, and phospholipids. Recent studies indicate that the phosphorylation state and amount of calmodulin bound to B-50 regulate the rate of transmitter release. Induction of long-term potentiation by high frequency stimulation of hippocampal slices results in an increased state of B-50 phosphorylation. This will increase the amount of free calmodulin in the presynaptic terminal and increase the amount of transmitter released. Although B-50 is involved in seemingly unrelated forms of neuronal plasticity, neurite outgrowth and transmitter release, our unifying hypothesis is that the protein plays an (unknown) essential, modulatory role in membrane expansion.