Regulation of norepinephrine synthesis - ScienceDirect

Reduction of the nitroethylatedindoles (2a-d) by hydrogenation over PtO2, followed by acetylationfo the resluting tryptamines with acetic anhydride-pyridine completed thesynthesis of melatonin and its derivatives (4a-d).

Biosynthesis of epinephrine and norepinephrine by sympathetic nerves and ganglia.

The simple structure of the neurotransmitters NE and 5HT invites comparisons between modes of monoamine recognition by receptors and transporters. In adrenergic receptors, the protonated NH group on NE is believed to ion pair with an intramembrane aspartate residue, while catechol OH groups form hydrogen bonds with serine residues on a nearby TMD (). Likewise, structural features of catecholamines required for high-affinity recognition by NETs and SERTs confirm the importance of ring hydroxyl groups and a protonated, unsubstituted NH group (). Furthermore, TMD aspartate and serine residues are among the handful of residues specific to the NET, SERT, DAT wing of the GAT/NET gene family, raising possibilities of similar strategies for the recognition of neurotransmitters by transporters and receptors (). Site-directed mutagenesis of the TMD1 aspartate residue in NET, SERT (R. D. Blakely, ), and DAT () markedly alters substrate and antagonist recognition. For DAT, retention of low-affinity cocaine binding and substrate recognition suggests a selective alteration in the ligand binding pocket by the aspartate mutation rather than a gross destabilization of transporter protein. Antibody studies reveal no difference between wild-type and TMD1 aspartate-mutant NET and SERT proteins, similarly consistent with a direct alteration at the binding site rather a global modification of protein stability. Nonetheless, the idea that the TMD1 aspartate residue directly coordinates the catecholamine NH group via salt-bridge formation is problematic in light of the fact that other GAT/NET proteins have an uncharged glycine residue in the position occupied by the NET, DAT, and SERT aspartate, and yet they bind substrates with protonated NH groups. Moreover, what is unique about NE, DA, and 5HT as GAT/NET substrates is not the presence of a protonated NH group to possibly bind the TMD1 aspartate, but rather the absence of an acidic side chain linked to the substrates' -carbon. One or more of the residues shared by NET, SERT, and DAT but not by other GAT/NET homologues, such as the TMD1 aspartate, may represent a binding site for the decarboxylated catecholamine and indoleamine substrates. Finally, the differential drug sensitivities observed between species variants of the same transporter may assist in the search for molecular determinants of antagonist binding. For example, the recent identification of a SERT that transports 5HT selectively but recognizes NET antagonists like mazindol with high affinity () may provide important clues to how antagonists bind and block transport.

Norepinephrine-induced synthesis of the uncoupling …

Synthesis of ACh occurs in the cytoplasm of cholinergic presynaptic terminals.

Analysis of the amino acid sequences of the cloned human SERT reveals six potential sites of phosphorylation by protein kinase A and protein kinase C (); five of these recognition sites also are conserved in rat SERT (,). Acute and chronic regulation of SERT by protein kinase C and cAMP have been reported, possibly involving one or more of these potential phosphorylation sites. Activation of protein kinase C with phorbol esters causes a dose-dependent inhibition of SERT activity in bovine pulmonary endothelial cells, platelets, and RBL cells that is blocked by protein kinase C inhibitors (, , ). However, in the RBL cell line, activation of adenosine receptors coupled to the phosphoinositide hydrolysis signaling pathway also should activate protein kinase C and, in contrast, increase SERT activity, suggesting differential regulation by protein kinase C and/or additional pathways engaged in these cells (). After cholera toxin and forskolin treatment, human placental choriocarcinoma (JAR) cells display enhanced SERT activity and increased cell-surface transporter density; however, the delayed nature of this effect compared to the rapid rise in intracellular cAMP levels suggests an effect on mRNA stability or gene transcription (). Indeed, the levels of SERT mRNA are markedly elevated by cholera toxin treatment (). The effects of cAMP on SERT expression may reflect a cell or species-specific sensitivity of the human SERT gene to second messengers in that increases in cAMP levels have been reported to induce down-regulation of SERT activity in rat PC12 cells and C33-14-B1 mouse fibroblasts (). Regardless, SERTs and NETs, like other molecules involved in neurotransmitter signaling, appear to be sensitive to chronic changes in intracellular regulatory cascades and could be inappropriately regulated in mental illness.