Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma membrane serotonin transporters (SERTs) regulate serotonin (5HT) levels in brain and are a site of action of antidepressants and psychostimulant drugs of abuse. Syntaxin 1A is a component of the synaptic vesicle docking and fusion apparatus and has been shown to interact with multiple plasma membrane neurotransmitter transporters including SERT. Previously, we showed that syntaxin 1A regulates the transport stoichiometry of SERT. When not bound to syntaxin 1A, SERT shows both substrate-independent Na(+) fluxes and substrate-dependent Na(+) fluxes of variable stoichiometry; these fluxes are eliminated in the presence of syntaxin 1A as Na(+) flux becomes strictly coupled to 5HT uptake. However, not known are the endogenous signaling molecules that determine the conducting states that SERT exhibits. In the present experiments, we show that inhibitors of calcium/calmodulin-dependent kinase II (CaM kinase II) modulate the stoichiometry of 5HT flux and that this effect requires syntaxin 1A. The modulation correlates with a shift in the affinity of SERT for syntaxin 1A binding. The regulation by CaM kinase II is eliminated by a mutation in the N-terminal domain of SERT. In neonatal thalomocortical neurons that endogenously express SERT and syntaxin 1A, inhibition of CaM kinase II reveals SERT-mediated currents. These data suggest that calcium-mediated signals can serve as a trigger for regulating protein-protein interactions that control SERT conducting states.
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PMID:Calcium/calmodulin-dependent kinase II regulates the interaction between the serotonin transporter and syntaxin 1A. 1860 29

Protein kinases are critical component in the regulation of signal transduction pathways, including neurotransmitters. Our previous studies have shown that serotonin (5-HT) altered under diabetic condition was accompanied by alterations of protein kinase C-alpha (PKC-alpha) and CaMKII, and those alterations were reversed after insulin administration. The current study showed that alloxan-induced diabetic animals revealed hyperglycemia and was associated with an increase in the content of 5-HT, PKC-alpha expression and PKC activity (P < 0.05) simultaneously in striatum (ST), midbrain (MB), pons medulla (PM), cerebellum (CB), and cerebral cortex (CCX) from 7 days to 60 days. Although the 5-HT levels in hippocampus (HC) and hypothalamus (HT) were not altered, the PKC-alpha expression and PKC activity showed increases (P < 0.05) in level in HC. Insulin administration reversed all these changes to a normal level. In contrast, the in vitro study has shown that the 5-HT levels correlated with PKC-alpha expressions as well as PKC activity (P < 0.05) only in ST, MB, and CB either after induction with phorbol 12-myristate 13-acetate (PMA) or blocking with chelerythrine, whereas PM and CCX remained elevated (P < 0.05), implying a regulatory role for PKC-alpha only in ST, MB, and CB. However, our consecutive studies have shown that the 5-HT level in PM was regulated by p38-mitogen-activated protein kinase (p38-MAPK) both in vivo and in vitro, whereas the 5-HT level in CCX was coregulated by S-100beta by protein-protein interaction with serotonin transporter (SERT) via 8-bromoadenosine 3',5'-cyclic monophosphate sodium salt (8-Br-cAMP)-induced cAMP/PKAII pathway(s).
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PMID:Regulation of protein kinases and coregulatory interplay of S-100beta and serotonin transporter on serotonin levels in diabetic rat brain. 1871 46

In the central nervous system, synaptic levels of the monoamine neurotransmitter serotonin are mainly controlled by the serotonin transporter (SERT), and drugs used in the treatment of various psychiatric diseases have SERT as primary target. SERT is a phosphoprotein that undergoes phosphorylation/dephosphorylation during transporter regulation by multiple pathways. In particular, activation and/or inhibition of kinases including PKC, PKG, p38MAPK, and CaMKII modulate SERT function and trafficking. The molecular mechanisms by which kinase activity is linked to SERT regulation are poorly understood, including the identity of specific phosphorylated residues. To elucidate SERT phosphorylation sites, we have generated peptides corresponding to the entire intracellular region of human SERT and performed in vitro phosphorylation assays with a panel of kinases suggested to be involved in SERT regulation or for which canonical phosphorylation sites are predicted. Peptide analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify and quantify site-specific phosphorylation. Five residues located in the N- and C-termini and in intracellular loop 1 and 2 were identified as phosphorylation sites; Ser149, Ser277, and Thr603 for PKC, Ser13 for CaMKII, and Thr616 for p38MAPK. Possible regulatory roles of these potential phosphoacceptors for SERT function and surface expression were investigated using phospho-mimicking and phosphodeficient mutations, coexpression of constitutively active kinases and pharmacological kinase induction in a heterologous expression system. Our results suggest that Ser277 is involved in an initial phase of PKC-mediated down-regulation of SERT. The five identified sites can guide future studies of direct links between SERT phosphorylation and regulatory processes.
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PMID:Characterization of intracellular regions in the human serotonin transporter for phosphorylation sites. 2445 Feb 86

Kappa opioid receptor (KOR) agonists produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent models. The cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects are not clear. KOR agonists modulate serotonin (5-HT) transmission in the brain regions implicated in mood and motivation regulation. Presynaptic serotonin transporter (SERT) activity is critical in the modulation of synaptic 5-HT and, subsequently, in mood disorders. Detailing the molecular events of KOR-linked SERT regulation is important for examining the postulated role of this protein in mood disorders. In this study, we used heterologous expression systems and native tissue preparations to determine the cellular signaling cascades linked to KOR-mediated SERT regulation. KOR agonists U69,593 and U50,488 produced a time and concentration dependent KOR antagonist-reversible decrease in SERT function. KOR-mediated functional down-regulation of SERT is sensitive to CaMKII and Akt inhibition. The U69,593-evoked decrease in SERT activity is associated with a decreased transport Vmax, reduced SERT cell surface expression, and increased SERT phosphorylation. Furthermore, KOR activation enhanced SERT internalization and decreased SERT delivery to the membrane. These data demonstrate that KOR activation decreases 5-HT uptake by altering SERT trafficking mechanisms and phosphorylation status to reduce the functional availability of surface SERT.
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PMID:Modulation of serotonin transporter function by kappa-opioid receptor ligands. 2774 31

Susceptibility to stress-related psychopathology is associated with reduced expression of the serotonin transporter (5-HTT), particularly in combination with stress exposure. Aberrant physiological and neuronal responses to threat may underlie this increased vulnerability. Here, implementing a cross-species approach, we investigated the association between 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance and action preparation. We tested this during threat anticipation induced by a well-established fear conditioning paradigm applied in both humans and rodents. In humans, we studied the effect of the common 5-HTT-linked polymorphic region (5-HTTLPR) on bradycardia and neural responses to anticipatory threat during functional magnetic resonance imaging scanning in healthy volunteers (n = 104). Compared with homozygous long-allele carriers, the 5-HTTLPR short-allele carriers displayed an exaggerated bradycardic response to threat, overall reduced activation of the medial prefrontal cortex (mPFC), and increased threat-induced connectivity between the amygdala and periaqueductal gray (PAG), which statistically mediated the effect of the 5-HTTLPR genotype on bradycardia. In parallel, 5-HTT knockout (KO) rats also showed exaggerated threat-related bradycardia and behavioral freezing. Immunohistochemistry indicated overall reduced activity of glutamatergic neurons in the mPFC of KO rats and increased activity of central amygdala somatostatin-positive neurons, putatively projecting to the PAG, which-similarly to the human population-mediated the 5-HTT genotype's effect on freezing. Moreover, the ventrolateral PAG of KO rats displayed elevated overall activity and increased relative activation of CaMKII-expressing projection neurons. Our results provide a mechanistic explanation for previously reported associations between 5-HTT gene variance and a stress-sensitive phenotype.
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PMID:The association between serotonin transporter availability and the neural correlates of fear bradycardia. 3177 23