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Nerve growth factor regulates the expression of the cholinergic locus and the high‐affinity choline transporter via the Akt/PKB signaling pathway
Author(s) -
Madziar Beata,
Shah Sonia,
Brock Martina,
Burke Rebecca,
LopezCoviella Ignacio,
Nickel AnnChristin,
Cakal Esra Betul,
Blusztajn Jan Krzysztof,
Berse Brygida
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05681.x
Subject(s) - choline acetyltransferase , cholinergic , nerve growth factor , protein kinase b , cholinergic neuron , biology , microbiology and biotechnology , acetylcholine , vesicular acetylcholine transporter , signal transduction , chemistry , endocrinology , biochemistry , receptor
Nerve growth factor (NGF) is a trophic and survival factor for cholinergic neurons, and it induces the expression of several genes that are essential for synthesis and storage of acetylcholine (ACh), specifically choline acetyltransferase, vesicular ACh transporter (VAChT), and choline transporter. We have found previously that the phosphatidylinositol 3′‐kinase pathway, but not the MEK/MAPK pathway, is the mediator of NGF‐induced cholinergic differentiation. Here we demonstrate, in the rat pheochromocytoma cell line PC12 and in primary mouse neuronal cultures, that NGF‐evoked up‐regulation of these three cholinergic‐specific genes is mediated by the anti‐apoptotic signaling molecule Akt/protein kinase B. Inhibition of Akt activation by the pharmacological inhibitor 1L‐6‐hydroxymethyl‐chiro‐inositol 2( R )‐2‐ O ‐methyl‐3‐ O ‐octadecylcarbonate (HIMO), or by a peptide fragment derived from the proto‐oncogene TLC1, eliminated NGF‐stimulated increases in cholinergic gene expression, as demonstrated by RT‐PCR and reporter gene assays. Moreover, treatment with HIMO reversed NGF‐evoked increases in choline acetyltransferase activity and ACh production. In co‐transfection assays with the reporter construct, a dominant‐negative Akt plasmid and Akt1‐specific small interfering RNA also attenuated NGF‐induced cholinergic promoter activity. Our data indicate that, in addition to its well‐described role in promoting neuronal survival, Akt can also mediate signals necessary for neurochemical differentiation.