GAP43 is a crucial component of the axon and presynaptic terminal. Its null mutation leads to death within days after birth, due to axon pathfinding defects.[7]
Synonyms
GAP43 is also referred to as:
protein F1
neuromodulin
neural phosphoprotein B-50
axonal membrane protein GAP-43
calmodulin-binding protein P-57
nerve growth-related peptide GAP43
neuron growth-associated protein 43
Function
GAP43, is a nervous tissue-specific cytoplasmic protein that can be attached to the membrane via a dual palmitoylation sequence on cysteines 3 and 4. This sequence targets GAP43 to lipid rafts. It is a major protein kinase C (PKC) substrate and is considered to play a key role in neurite formation, regeneration, and plasticity.[8][9] The role of GAP-43 in CNS development is not limited to effects on axons: It is also a component of the centrosome, and differentiating neurons that do not express GAP-43 show mislocalization of the centrosome and mitotic spindles, particularly in neurogenic cell divisions. As a consequence, in the cerebellum, the neuronal precursor pool fails to expand normally and the cerebellum is significantly smaller.[10]
Several different laboratories studying the same protein, now called GAP43, initially used different names. It was designated F1, then B-50, then GAP43, pp46, and finally neuromodulin, each name reflecting a different function of the same molecule.[11] F1 was localized to synapses, and was increased in its phosphorylation one day after learning. However, F1 was not cAMP kinase dependent. B-50 was regulated by the pituitary peptide ACTH and was associated with grooming behavior. In the case of GAP-43, it was designated as a growth-associated protein because its synthesis was upregulated during axonal regeneration. Pp46 was concentrated in neuronal growth cones and was thus postulated to play an important role in brain development. In the case of neuromodulin, it was shown to bind calmodulin avidly.
GAP43, the consensus choice for its designation,[11] is a nervous system-specific protein that is attached to the membrane via a dual palmitoylation sequence on cysteines 3 and 4, though it can exist in the non-bound form in the cytoplasm. This dual sequence enables the association of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] or PIP2, with actin, facilitating the latter's polymerization thereby regulating neuronal structure. This can occur within a lipid raft so as to compartmentalize and localize motility of filopodia in growth cones in developing brains, and could also remodel presynaptic terminals in adults in an activity-dependent manner. GAP-43 is also a protein kinase C (PKC) substrate. Phosphorylation of serine-41 on GAP-43 by PKC regulates neurite formation, regeneration, and synaptic plasticity.[8]
Because of the association and potential binding of GAP43 with a number of different molecules, including PKC, PIP2, actin, calmodulin, spectrin, palmitate, synaptophysin, amyloid and tau protein, it may be useful to think of GAP43 as an adaptor protein situated within the terminal in a supramolecular complex regulating presynaptic terminal functions, particularly bidirectional communication with the postsynaptic process. Its important role in memory and information storage is executed through its cell biological mechanisms of phosphorylation, palmitoylation, protein-protein interaction and structural remodeling via actin polymerization.
Clinical significance
Humans with a deletion in one allele of the GAP43 gene fail to form telencephalic commissures and are intellectually disabled.[12][13]
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^ abBenowitz LI, Routtenberg A (1987). "A membrane phosphoprotein associated with neural development, axonal regeneration, phospholipid metabolism, and synaptic plasticity". Trends in Neurosciences. 10 (12): 527–532. doi:10.1016/0166-2236(87)90135-4. S2CID54322365.
^Genuardi M, Calvieri F, Tozzi C, Coslovi R, Neri G (Oct 1994). "A new case of interstitial deletion of chromosome 3q, del(3q)(q13.12q21.3), with agenesis of the corpus callosum". Clinical Dysmorphology. 3 (4): 292–6. doi:10.1097/00019605-199410000-00003. PMID7894733. S2CID38716384.
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Nielander HB, De Groen PC, Eggen BJ, Schrama LH, Gispen WH, Schotman P (Sep 1993). "Structure of the human gene for the neural phosphoprotein B-50 (GAP-43)". Brain Research. Molecular Brain Research. 19 (4): 293–302. doi:10.1016/0169-328X(93)90128-C. hdl:1874/4067. PMID8231732.
Kanazir S, Ruzdijic S, Vukosavic S, Ivkovic S, Milosevic A, Zecevic N, Rakic L (May 1996). "GAP-43 mRNA expression in early development of human nervous system". Brain Research. Molecular Brain Research. 38 (1): 145–55. doi:10.1016/0169-328X(96)00008-3. PMID8737678.
de Groen PC, Eggen BJ, Gispen WH, Schotman P, Schrama LH (1996). "Cloning and promoter analysis of the human B-50/GAP-43 gene". Journal of Molecular Neuroscience. 6 (2): 109–19. doi:10.1007/BF02736770. PMID8746449. S2CID22911100.
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