Modulation of Serotonin Transporter Activity by a Protein Kinase C Activator and an Inhibitor of Type 1 and 2A Serine/Threonine Phosphatases

Sakai, Norio; Sasaki, Keiko; Nakashita, Mayumi; Honda, Shigeru; Ikegaki, Natsu; Saito, Naoaki

doi:10.1046/j.1471-4159.1997.68062618.x

Cited by 56 publications

(25 citation statements)

References 19 publications

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“…Although these studies show that the DAT contains consensus sequences for recognition by PKC, and that DAT activity can be modified by phosphorylation, the relevant phosphorylation sites that alter DAT expression are not necessarily on the DAT itself. Work on the GAT1 ␥-aminobutyric acid transporter (Corey et al, 1994) and the GLYT1 glycine transporter (Sato et al, 1995), two transporters that, similarly to DAT, contain PKC sequences, showed that when all predicted intracellular PKC sites were mutated, regulation by PKC was left intact, demonstrating that regulation might occur indirectly via other proteins that serve scaffolding or trafficking functions (Sakai et al, 1997). Recently, similar results have been found for the DAT, which also exhibits normal transporter kinetics and trafficking patterns even when all PKC consensus sites on the transporter itself are mutated (Chang et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

ς2-Receptor Regulation of Dopamine Transporter via Activation of Protein Kinase C

Derbez

Mody²,

Werling³

2002

The Journal of Pharmacology and Experimental Therapeutics

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The elucidation of the mechanisms underlying 2 -receptor activation and signal transduction is crucial to the understanding of 2 -receptor function. Previous studies in our laboratory have demonstrated 2 -receptor-mediated regulation of the dopamine transporter (DAT) as measured by amphetamine-stimulated release of [ -Receptors were first identified in 1976 by Martin et al. (1976) as the sites through which the psychotomimetic effects of SKF10,047 were mediated. Since that time, progress in identifying their physiological function(s) has been relatively slow compared with other receptor systems. There are at least two types of -receptors, designated 1 and 2 (Hellewell and Bowen, 1990;Quirion et al., 1992). -Receptors are distributed widely in the periphery and central nervous system (Walker et al., 1990). In brain, they are localized especially in motor and limbic systems (Gundlach et al., 1986), areas typically subserved by catecholaminergic neurotransmission. 1 -and 2 -receptors are colocalized in most regions, and have been reported to be present in a ratio of 4.3:1 in striatum (Bouchard and Quirion, 1997). 1 -Receptors were cloned first from guinea pig liver by Hanner et al. (1996) and the corresponding human gene further characterized by Prasad et al. (1998).1 -Receptors have been associated with second messenger activation and inhibition in several model systems. There is disagreement whether 1 -receptors are coupled through G

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Section: Discussionmentioning

confidence: 99%

ς2-Receptor Regulation of Dopamine Transporter via Activation of Protein Kinase C

Derbez

Mody²,

Werling³

2002

The Journal of Pharmacology and Experimental Therapeutics

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“…This decrease of maximal transport activity is a consequence of SERT internalization from the plasma membrane into endocytosis vesicles [9]. In previous results, the phosphorylation-mediated reduction of serotonin uptake was found to be maintained even upon mutation of all pre-dicted phosphorylation sites in the SERT polypeptide [29].…”

Section: Discussionmentioning

confidence: 78%

“…An interesting question is how N-terminal phosphorylation of SERT regulates the activity of SERT. In previous pharmacological studies, the recombinant SERT expressed in cells failed to reveal changes in substrate transport after PKA activation, and stimulation of PKC has been shown to result in a reduction of maximal transport activity without alterations in substrate affinity [25,29]. This decrease of maximal transport activity is a consequence of SERT internalization from the plasma membrane into endocytosis vesicles [9].…”

Section: Discussionmentioning

confidence: 99%

“…SERT also has consensus sequences for potential phosphorylation sites by protein kinases [6,20]. In many pharmacological studies, SERT uptake activity was shown to be modulated by PKA, PKC and other protein kinases [25,27,29]. Activation of PKA has been shown to up-regulate the transport activity of the SERT via increased synthesis of the SERT, rather than the direct phosphorylation of the SERT [5,20].…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, several protein kinase could phosphortlate the serine residues of SERT N-terminal [29]. To clarify whether PKC-ε directly phosphorylates the SERT, we tested the ability of PKC-ε to incorporate phosphate into a peptide corresponding to the first N-terminal 25 residues of SERT.…”

Section: Pkc-ε Phosphorylates the Sert N-terminusmentioning

confidence: 99%

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Protein Kinase (PKC)-ε Interacts with the Serotonin Transporter (SERT) C-Terminal Region

Moon¹,

Seog

2010

Journal of Life Science

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Serotonin (5-hydroxytryptamine, 5-HT) is an important mediator of cell-cell signaling in neuronal systems. The serotonin transporter (SERT) on the plasma membrane controls the extracellular 5-HT level by reuptake of released 5-HT from the synaptic cleft, but the underlying regulation mechanism is unclear. Here, we used the yeast two-hybrid system to identify the specific binding protein(s) that interacts with the carboxyl (C)-terminal region of SERT and found a specific interaction with protein kinase C-ε (PKC-ε), a PKC isotype that is characterized as a calcium-independent and phorbol ester/diacylglycerol-sensitive serine/threonine kinase. PKC-ε bound to the tail region of SERT but not to other members of the Na + /Cl -dependent SLC6 gene family in the yeast two-hybrid assay. The C-terminal region of PKC-ε is essential for interaction with SERT. In addition, these proteins showed specific interactions in the glutathione S-transferase (GST) pull-down assay. PKC-ε phosphorylated the peptide of the SERT amino (N)-terminus in vitro. These results suggest that the phosphorylation of SERT by PKC-ε may regulate SERT activity in plasma membrane.

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1‐Stearoyl‐2‐docosahexaenoyl‐phosphatidic acid interacts with and activates Praja‐1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain

Lü

Murakami

et al. 2020

FEBS Letters

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Edited by Sandro SonninoSerotonin transporter (SERT) is involved in serotonergic system regulation and in the pathophysiology/therapeutics of serotonin-/SERT-related diseases such as obsessive-compulsive disorder, depression, autism, and schizophrenia. We recently revealed that diacylglycerol (DG) kinase (DGK) d induces ubiquitination/degradation of SERT in a DGK activity-dependent manner through Praja-1 E3 ubiquitin-protein ligase. However, it is still unclear how Praja-1 activity is regulated by DGKd. Here, we reveal that 1-stearoyl-2-docosahexaenoyl (18:0/22:6)-phosphatidic acid (PA) and 18:0/22:6-DG are simultaneously decreased and accumulated, respectively, in the DGKd-knockout mouse brain, indicating that DGKd selectively phosphorylates 18:0/22:6-DG to generate 18:0/22:6-PA. Moreover, we find that 18:0/22:6-PA selectively binds to Praja-1 and enhances its activity. These results strongly suggest that 18:0/ 22:6-PA generated by DGKd activates Praja-1 to degrade SERT in the brain.Keywords: diacylglycerol kinase; docosahexaenoic acid; E3 ubiquitinprotein ligase; obsessive-compulsive disorder; Praja-1; serotonin transporter Serotonin/5-hydroxytryptamine (5-HT) is known to be involved in anxiety, depression, compulsiveness, and impulsivity [1]. The serotonin/5-HT transporter (SERT) reuptakes 5-HT from the synaptic cleft into the presynaptic neuron for recycling and metabolic degradation [2,3]. Selective serotonin reuptake (SERT) inhibitors (SSRIs) are used for the treatment of obsessive-compulsive disorder (OCD) [2,3] and major depressive disorder [4]. Several studies using SERTdeficient rodents have demonstrated that SERT is implicated in neurodevelopmental disorders, such as depression, anxiety, and autism [5]. Therefore, hyperfunction of SERT, which reduces the amount of 5-HT in the synaptic cleft, causes various psychiatric disorders mentioned above. However, the regulatory mechanisms of SERT function are still obscure.Diacylglycerol (DG) kinase (DGK), which consists of ten isozymes (a-j), is a lipid-metabolizing enzyme that phosphorylates DG to generate phosphatidic acid (PA) [6][7][8][9][10]. DG and PA are established lipid second messengers that regulate a wide variety of physiological and pathological events.

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Modulation of Serotonin Transporter Activity by a Protein Kinase C Activator and an Inhibitor of Type 1 and 2A Serine/Threonine Phosphatases

Cited by 56 publications

References 19 publications

ς2-Receptor Regulation of Dopamine Transporter via Activation of Protein Kinase C

ς2-Receptor Regulation of Dopamine Transporter via Activation of Protein Kinase C

Protein Kinase (PKC)-ε Interacts with the Serotonin Transporter (SERT) C-Terminal Region

1‐Stearoyl‐2‐docosahexaenoyl‐phosphatidic acid interacts with and activates Praja‐1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain

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