BACKGROUND Growth-associated protein-43 (GAP-43), a neurite growth potentiator, is a nervous system specific F-actin regulating phosphoprotein expressed during development that enables differentiating neurons to respond to extracellular signals. GAP-43 also plays a role in sprouting responses associated with adult plasticity. GAP-43 is expressed along with BDNF in response to neuronal injuries and is upregulated in granule cells following BDNF treatment. It was shown that GAP-43 is an essential downstream effector of positive AMPA receptor modulators and subsequent BDNF-induced responses.1 In addition, GAP-43 plays important role in neural cell adhesion molecule (NCAM)-mediated regulation ofn actin cytoskeletal dynamics. By binding to the fibroblast growth factor receptor (FGFR), NCAM activates intracellular pathways to trigger calcium release, lipid diacylglycerol (DAG) formation, and protein kinase C (PKC) activation to specifically phosphorylate GAP-43 on serine 41. Phosphorylated GAP-43 plays a key role in neurite outgrowth, presumably by promoting actin polymerization. Of all NCAM isoforms, only NCAM-180 takes part in this GAP-43-dependent neurite outgrowth. GAP-43 and NCAM-180 are found in the same plasma membrane domains (rafts), and these two proteins form a functional complex with spectrin that may control cytoskeleton dynamics to induce neurite outgrowth. In addition, it was also shown that modification of GAP-43 at its PKC phosphorylation site directs its distribution to different membrane microdomains that have distinct roles in the regulation of intrinsic and extrinsic behaviors in growing neurons.2 In the absence of GAP-43, the signaling pathway that depends on NCAM-140 and nonreceptor tyrosine kinase (Fyn) is activated.3
1. Gupta, S.K. et al: Cell Death Diff. 16: 624–637, 2009
2. Nguyen, L. et al: Mol. Cell. Neurosci. 41:62-73, 2009
3. Korshunova, I. & Mosevitsky, M.:Adv. Exp. Med. Biol. 663:169-82, 2010
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