Differential regulation of the high affinity choline transporter and the cholinergic locus by cAMP signaling pathways

Abstract

Synthesis, storage and release of acetylcholine (ACh) require the expression of several specialized enzymes, including choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT) and the high-affinity choline transporter (CHT). Extracellular factors that regulate CHT expression and their signaling pathways remain poorly characterized. Using the NSC-19 cholinergic cell line, derived from embryonic spinal cord, we compared the effects of the second messenger cAMP on the expression of CHT and the cholinergic locus containing the ChAT and VAChT genes. Treatment of NSC-19 cells with dbcAMP and forskolin, thus increasing intracellular cAMP levels, significantly reduced CHT mRNA expression, while it upregulated ChAT/VAChT mRNA levels and ChAT activity. The cAMP-induced CHT downregulation was independent of PKA activity, as shown in treatments with the PKA inhibitor H-89. The alternative Epac-Rap pathway, when stimulated by a specific Epac activator, led to significant downregulation of CHT and ChAT, and, to a lesser extent, VAChT. In contrast, the PKA activator 6-BNZ-cAMP stimulated the expression of all three genes, but with varying concentration-dependence profiles. Our results indicate that elevations of intraneuronal cAMP concentration have differential effects on the cholinergic phenotype, depending on the involvement of different downstream effectors. Interestingly, although CHT is expressed predominantly in cholinergic cells, its regulation appears to be distinct from that of the cholinergic locus.

Cholinium-based ionic liquids with pharmaceutically active anions

“…34 Because of the prevalence of cholinium in the human body, cholinium-based API-ILs have been prepared and investigated within the frame of this work for their potential use in pharmaceutical applications. Plus, cholinium salts such as the chloride ([N 1112OH ]Cl -the cation "supplier", cf.…”

Crosstalk among electrical activity, trophic factors and morphogenetic proteins in the regulation of neurotransmitter phenotype specification

“…The mechanisms of BMP-induced cholinergic specification in mice and rat basal forebrain may involve the upregulation of c-Fos expression (Lopez-Coviella et al, 2005), which in turn enhances expression of the cholinergic phenotype genes, ChAT, VAChT and AChE (Kaufer et al, 1998). Trophic factors like NGF also regulate the expression of the cholinergic phenotype in the rat pheochromocytoma cell line (PC12) and in primary neuronal cultures from the mouse embryonic septum, potentially by recruiting the Akt/PI3K pathway and by regulating GSK3 activity (Madziar et al, 2008), which in turn may control CREB activity that also regulates the expression of the cholinergic locus in mouse and rat neurons (Brock et al, 2007; Liu et al, 2008). …”

Biocompatible Ionic Liquid–Biopolymer Electrolyte-Enabled Thin and Compact Magnesium–Air Batteries

“…[24][25][26] This is mostly due to the fact that choline (more correctly cholinium) is a naturally occurring cation that shows very low toxicity and it can work as a cell signaling agent. 27,28 Choline salts have also been used recently in IL-gel systems for cancer therapy delivery. 29 Choline nitrate, [Ch][NO3], is chosen in this work due to its low viscosity, high conductivity and biocompatibility.…”