Targeting of the 5-HT1A Serotonin Receptor to Neuronal Dendrites Is Mediated by Yif1B (original) (raw)
Related papers
Journal of Psychiatry and Neuroscience, 2020
Background: Altered function of serotonin receptor 1A (5-HT 1A R) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT 1A R (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT 1A R trafficking may also be involved. Methods: We investigated the consequences of the lack of Yif1B (the 5-HT 1A R trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice. Results: Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT 1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive disorder and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys. Limitations: We found sex differences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions. Conclusion: These data support the concept that Yif1B plays a critical role in 5-HT 1A R functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficacy.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012
Although essential for their neuronal function, the molecular mechanisms underlying the dendritic targeting of serotonin G-protein-coupled receptors are poorly understood. Here, we characterized a Yif1B-dependent vesicular scaffolding complex mediating the intracellular traffic of the rat 5-HT(1A) receptor (5-HT(1A)R) toward dendrites. By combining directed mutagenesis, GST-pull down, and surface plasmon resonance, we identified a tribasic motif in the C-tail of the 5-HT(1A)R on which Yif1B binds directly with high affinity (K(D) ≈ 37 nM). Moreover, we identified Yip1A, Rab6, and Kif5B as new partners of the 5-HT(1A)R/Yif1B complex, and showed that their expression in neurons is also crucial for the dendritic targeting of the 5-HT(1A)R. Live videomicroscopy revealed that 5-HT(1A)R, Yif1B, Yip1A, and Rab6 traffic in vesicles exiting the soma toward the dendritic tree, and also exhibit bidirectional motions, sustaining their role in 5-HT(1A)R dendritic targeting. Hence, we propose a n...
What Do We Really Know About 5-HT1A Receptor Signaling in Neuronal Cells?
Frontiers in cellular neuroscience, 2016
Serotonin (5-HT) is a neurotransmitter that plays an important role in neuronal plasticity. Variations in the levels of 5-HT at the synaptic cleft, expression or dysfunction of 5-HT receptors may alter brain development and predispose to various mental diseases. Here, we review the transduction pathways described in various cell types transfected with recombinant 5-HT1A receptor (5-HT1AR), specially contrasting with those findings obtained in neuronal cells. The 5-HT1AR is detected in early stages of neural development and is located in the soma, dendrites and spines of hippocampal neurons. The 5-HT1AR differs from other 5-HT receptors because it is coupled to different pathways, depending on the targeted cell. The signaling pathway associated with this receptor is determined by Gα isoforms and some cascades involve βγ signaling. The activity of 5-HT1AR usually promotes a reduction in neuronal excitability and firing, provokes a variation in cAMP and Ca(2+), levels which may be link...
5-HT 1B autoreceptor regulation of serotonin transporter activity in synaptosomes
Synapse, 2012
Serotonin-1B (5-HT 1B ) autoreceptors are located in serotonin (5-HT) terminals, along with serotonin transporters (SERT), and play a critical role in autoregulation of serotonergic neurotransmission and are implicated in disorders of serotonergic function, particularly emotional regulation. SERT modulates serotonergic neurotransmission by high-affinity reuptake of 5-HT. Alterations in SERT activity are associated with increased risk for depression and anxiety. Several neurotransmitter receptors are known to regulate SERT K m and V max , and previous work suggests that 5-HT 1B autoreceptors may regulate 5-HT reuptake, in addition to modulating 5-HT release and synthesis. We used rotating disk electrode voltammetry to investigate 5-HT 1B autoreceptor regulation of SERT-mediated 5-HT uptake into synaptosomes. The selective 5-HT 1B antagonist SB224289 decreased SERT activity in synaptosomes prepared from wild-type but not 5-HT 1B knockout mice, whereas SERT uptake was enhanced after pretreatment with the selective 5-HT 1B agonist CP94253. Furthermore, SERT activity varies as a function of 5-HT 1B receptor expression-specifically, genetic deletion of 5-HT 1B decreased SERT function, while viral-mediated overexpression of 5-HT 1B autoreceptors in rat raphe neurons increased SERT activity in rat hippocampal synaptosomes. Considered collectively, these results provide evidence that 5-HT 1B autoreceptors regulate SERT activity. Because SERT clearance rate varies as a function of 5-HT 1B autoreceptor expression levels and is modulated by both activation and inhibition of 5-HT 1B autoreceptors, this dynamic interaction may be an important mechanism of serotonin autoregulation with therapeutic implications.
Novel and atypical pathways for serotonin signaling
Faculty Reviews, 2021
Serotonin (5-HT) appeared billions of years before 5-HT receptors and synapses. It is thus not surprising that 5-HT can control biological processes independently of its receptors. One example is serotonylation, which consists of covalent binding of 5-HT to the primary amine of glutamine. Over the past 20 years, serotonylation has been involved in the regulation of many signaling mechanisms. One of the most striking examples is the recent evidence that serotonylation of histone H3 constitutes an epigenetic mark. However, the pathophysiological role of histone H3 serotonylation remains to be discovered. All but one of the 5-HT receptors are G-protein-coupled receptors (GPCRs). The signaling pathways they control are finely tuned, and new, unexpected regulatory mechanisms are being uncovered continuously. Some 5-HT receptors (5-HT 2C , 5-HT 4 , 5-HT 6 , and 5-HT 7) signal through mechanisms that require neither G-proteins nor β-arrestins, the two classical and almost universal GPCR signal transducers. 5-HT 6 receptors are constitutively activated via their association with intracellular GPCR-interacting proteins (GIPs), including neurofibromin 1, cyclin-dependent kinase 5 (Cdk5), and G-protein-regulated inducer of neurite outgrowth 1 (GPRIN1). Interactions of 5-HT 6 receptor with Cdk5 and GPRIN1 are not concomitant but occur sequentially and play a key role in dendritic tree morphogenesis. Furthermore, 5-HT 6 receptor-mediated G-protein signaling in neurons is different in the cell body and primary cilium, where it is modulated by smoothened receptor activation. Finally, 5-HT 2A receptors form heteromers with mGlu 2 metabotropic glutamate receptors. This heteromerization results in a specific phosphorylation of mGlu 2 receptor on a serine residue (Ser 843) upon agonist stimulation of 5-HT 2A or mGlu 2 receptor. mGlu 2 receptor phosphorylation on Ser 843 is an essential step in engagement of G i/o signaling not only upon mGlu 2 receptor activation but also following 5-HT 2A receptor activation, and thus represents a key molecular event underlying functional crosstalk between both receptors.
Neuroscience, 2002
öAs visualized by light and electron microscopic immunocytochemistry, the distribution of the neuronal serotonin-2A (5-HT 2A) receptor is mainly intracellular throughout adult rat brain. This localization is particularly striking in the pyramidal cells of cerebral cortex, the dendrites of which are intensely immunoreactive, but without any labeling of their spines. In view of recent yeast two-hybrid and biochemical results suggesting an association of 5-HT 2A receptors with the cytoskeletal microtubule-associated protein MAP1A, the respective subcellular distributions of the receptors and of MAP1A were compared by quantitative electron microscopic immunocytochemistry in dendrites of adult rat frontoparietal cortex. Counts of silver-intensi¢ed immunogold particles revealed a higher density of 5-HT 2A receptors in smaller rather than larger dendrites, and an apportionment between pre-de¢ned compartments representing the plasma membrane and the cytoplasm that was proportional to the relative surface area of these compartments. MAP1A immunoreactivity also predominated in smaller versus larger dendrites, but with a slightly lower proportion of labeling in the plasma membrane versus cytoplasmic compartment. The co-localization of 5-HT 2A receptors and MAP1A protein in the same dendrites could be demonstrated in double immunolabeling experiments. These results con¢rmed the predominantly somato-dendritic, intracellular localization of 5-HT 2A receptors in cerebral cortex, showed their higher concentration in distal as opposed to proximal dendrites, and suggested their potential association to the cytoskeleton in cortical neurons in vivo. Such a distribution of 5-HT 2A receptors reinforces our earlier hypothesis that 5-HT 2A receptors participate in intraneuronal signaling processes involving the cytoskeleton, and raises the possibility that their activation could be dependent upon that of another co-localized, plasma membrane-bound, 5-HT receptor.
Journal of Cell Science, 2012
Serotonin receptors 5-HT1A and 5-HT7 are highly co-expressed in brain regions implicated in depression. However, their functional interaction has not been established. In the present study we show that 5-HT1A and 5-HT7 receptors form heterodimers both in vitro and in vivo. Foerster resonance energy transfer-based assays revealed that, in addition to heterodimers, homodimers composed either by 5-HT1A or 5-HT7 receptors together with monomers co-exist in cells. The highest affinity to form the complex was obtained for the 5-HT7-5-HT7 homodimers, followed by the 5-HT7-5-HT1A heterodimers and 5-HT1A-5-HT1A homodimers. Functionally, heterodimerization decreases 5-HT1A receptor-mediated activation of Gi-protein without affecting 5-HT7 receptor-mediated signalling. Moreover, heterodimerization markedly decreases the ability of the 5-HT1A receptor to activate G-protein gated inwardly rectifying potassium channels in a heterologous system. The inhibitory effect on such channels was also pres...
Going with the Flow: Trafficking-Dependent and -Independent Regulation of Serotonin Transport
Traffic, 2008
Antidepressant-, cocaine-and 3,4-methylenedioxymethamphetamine-sensitive serotonin (5hydroxytryptamine, 5-HT) transporters (SERTs) are expressed on presynaptic membranes of 5-HTsecreting neurons to provide efficient uptake of the biogenic amine after release. SERTs also support 5-HT transport across platelet, placental, gastrointestinal and pulmonary membranes and thus play a critical role in central nervous system and peripheral nervous system 5-HT signaling. SERTs are subject to multiple levels of posttranslational regulation that can rapidly alter 5-HT uptake and clearance rates. Specific cell surface receptors are now known to regulate SERT trafficking and/or catalytic function, with pathways activating protein kinase C, protein kinase G and p38 mitogenactivated protein kinase receiving the greatest attention. Remarkably, disease-associated mutations in SERT not only impact basal SERT activity but also selectively impact one or more SERT regulatory pathway(s). In this review, we describe both trafficking-dependent and traffickingindependent modes of SERT regulation and also the suspected roles played in regulation by SERTassociated proteins. Elucidation of the SERT 'regulome' provides important depth to our understanding of the likely origins of 5-HT-associated disorders and may help orient research to develop novel therapeutics.
Neuroscience, 2003
The 5-HT 2A serotonin receptor represents an important molecular target for atypical antipsychotic drugs and for most hallucinogens. In the mammalian cerebral cortex, 5-HT 2A receptors are enriched in pyramidal neurons, within which 5-HT 2A receptors are preferentially sorted to the apical dendrites. In primary cortical cultures, 5-HT 2A receptors are sorted to dendrites and not found in the axons of pyramidal neurons. We identified a sorting motif that mediates the preferential targeting of 5-HT 2A receptors to the dendrites of cortical pyramidal neurons in vitro. We constructed green fluorescent protein-tagged 5-HT 2A receptors wherein potential sorting motifs were disrupted, and subsequently employed either the Semliki Forest virus or calcium phosphate for the transient expression of recombinant 5-HT 2A receptors in cultured cortical pyramidal neurons. Using dual-labeling immunofluorescent confocal microscopy, we quantified the axonal and dendritic sorting patterns of endogenous and recombinant 5-HT 2A receptors. We discovered that disruption of the PDZ-binding domain of the 5-HT 2A receptor greatly attenuates the dendritic targeting of 5-HT 2A receptors without inappropriately sorting 5-HT 2A receptors to axons. The PDZbinding domain is therefore a necessary signal for the preferential targeting of the 5-HT 2A receptor to the dendritic compartment of cultured cortical pyramidal neurons, the first such role ascribed to this protein-protein interaction motif of any G protein-coupled receptor.
Differential addressing of 5-HT1A and 5-HT1B receptors in epithelial cells and neurons
Journal of Cell Science, 1999
The 5-HT1A and 5-HT1B serotonin receptors are expressed in a variety of neurons in the central nervous system. While the 5-HT1A receptor is found on somas and dendrites, the 5-HT1B receptor has been suggested to be localized predominantly on axon terminals. To study the intracellular addressing of these receptors, we have used in vitro systems including Madin-Darby canine kidney (MDCK II) epithelial cells and primary neuronal cultures. Furthermore, we have extended these studies to examine addressing in vivo in transgenic mice. In epithelial cells, 5-HT1A receptors are found on both apical and basolateral membranes while 5-HT1B receptors are found exclusively in intracellular vesicles. In hippocampal neuronal cultures, 5-HT1A receptors are expressed on somatodendritic membranes but are absent from axons. In contrast, 5-HT1B receptors are found on both dendritic and axonal membranes, including growth cones where they accumulate. Using 5-HT1A and 5-HT1B knockout mice and the binary tT...