p38 MAPK Activation Elevates Serotonin Transport Activity via a Trafficking-independent, Protein Phosphatase 2A-dependent Process

Abstract

The indoleamine 5-hydroxytryptamine (serotonin, 5-HT) 1 plays a pivotal, modulatory role in a variety of centrally controlled physiological processes, including respiration, arousal, aggression, and mood, and in the periphery supports gastrointestinal, platelet, and placental function (1). 5-HT is inactivated following vesicular release by a presynaptic, antidepressant-sensitive 5-HT transporter (SERT, 5-HTT), a member of the Na ϩ /Cl Ϫ -dependent solute transporter family (SLC6A4) (2-4). SERT knock-out mice display altered presynaptic 5-HT homeostasis, modified 5-HT receptor sensitivities, and stressdependent behavioral modulation as well as altered responses to psychostimulants (5). In humans, altered SERT gene expression and/or transport function have been linked to multiple disorders including autism, obsessive-compulsive disorder, depression, and suicide (6 -11).Previous studies have demonstrated that both genetic and posttranscriptional processes regulate SERT activity (12, 13). SERT activity in native cells and transfected models can be rapidly (in minutes) modulated by multiple signaling pathways (14, 15). Observations with transfected HEK cells expressing human SERT (hSERT) demonstrated that protein kinase C activators or protein phosphatase 1/2A inhibitors trigger hSERT phosphorylation and a parallel decrease in hSERT cell surface density, effects that can be attenuated by . Protein kinase A and protein kinase G (PKG) activation can also trigger SERT phosphorylation (17), although the functional consequences of these stimuli are only beginning to be appreciated. SERTs appear to form homomultimers at the plasma membrane (19) and also interact with a growing list of associated proteins, including syntaxin 1A (20 -22)

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

“…This pathway has previously been implicated in the acute regulation of SERT activity in vitro [27,45,46] and in vivo [28,47,48]. Our data presented here suggest that p38 MAPK is also involved in the chronic regulation of SERT activity upon pro-longed cytokine exposure.…”

Molecular Genetics of the Platelet Serotonin System in First-Degree Relatives of Patients with Autism

“…This association suggests that the TT haplotype may be in LD with a functional variant or variants elsewhere in the gene or may itself have some unknown functional significance. The functional variant(s) could alter gene expression, protein trafficking, or protein regulation (Lesch et al, 1996;Prasad et al, 2005), and may demonstrate its platelet phenotype indirectly as a regulatory response to altered SERT structure or function (Jayanthi et al, 2005;Zhu et al, 2005;Carneiro and Blakely, 2006). The two most commonly observed amino-acid changes, Gly56Ala and Ile425Val, do not account for the association in this sample.…”

Hypothalamic-pituitary-adrenal axis function during perinatal depression

“…They also modify the inhibitory GABAergic inputs targeting PVN/ CRH neurons [96][97][98] . Thus, GCs display an intrinsic control of both CRH and AVP activity, including ACTH secretion from corticotrophs [99] . Genomic actions of GCs are mediated by the transcriptional activation or repression of target genes after translocation of the intracellular (ligandbound) receptor to the nucleus and binding of the receptor complex to a GC response element sequence located in the promoter region of GC-regulated genes [84,[100][101] .…”