Stimulation of Type 1 and Type 8 Ca2+/Calmodulin-sensitive Adenylyl Cyclases by the Gs-coupled 5-Hydroxytryptamine Subtype 5-HT7AReceptor

Baker, Lauren P.; Nielsen, Mark D.; Impey, Soren; Metcalf, Mark A.; Poser, Steven; Chan, Guy C.‐K.; Obrietan, Karl; Hamblin, Mark W.; Storm, Daniel R.

doi:10.1074/jbc.273.28.17469

Cited by 91 publications

(50 citation statements)

References 56 publications

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“…The mechanism by which the 5-HT7 receptors activate ERK1/2 has not been completely elucidated. According to some authors, activation of ERK1/2 is likely to occur as a consequence of the increase in both cAMP and calcium following activation of Gscoupled 5-HT7Rs (Baker et al, 1998). Indeed, treatment with inhibitors of either calcium or adenylyl cyclase interferes with the 5-HT7R-mediated ERK activation (Guseva et al, 2014).…”

Section: Mechanismmentioning

confidence: 99%

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

et al. 2016

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The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum

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Section: Mechanismmentioning

confidence: 99%

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

et al. 2016

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“…Culture-It has been reported that 5-HT 7 receptors are positively coupled to adenylyl cyclases, and the activation of 5-HT 7 receptors can stimulate adenylyl cyclases by increasing intracellular Ca 2ϩ (47). To further explore the role of cAMP in neuronal excitotoxicity, we next tested the effect of a 5-HT 7 receptor agonist AS 19 (48,49) in cultured cortical neurons.…”

Section: -Ht 7 Receptor Activation Does Not Induce Cell Death In Neumentioning

confidence: 99%

Genetic Evidence for Adenylyl Cyclase 1 as a Target for Preventing Neuronal Excitotoxicity Mediated by N-Methyl-D-aspartate Receptors

Wang

Gong

Vadakkan

et al. 2007

Journal of Biological Chemistry

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The excessive activation of N-methyl-D-aspartate (NMDA) receptors by glutamate results in neuronal excitotoxicity. cAMP is a key second messenger and contributes to NMDA receptordependent synaptic plasticity. Adenylyl cyclases 1 (AC1) and 8 (AC8) are the two major calcium-stimulated ACs in the central nervous system. Previous studies demonstrate AC1 and AC8 play important roles in synaptic plasticity, memory, and persistent pain. However, little is known about the possible roles of these two ACs in glutamate-induced neuronal excitotoxicity. Here, we report that genetic deletion of AC1 significantly attenuated neuronal death induced by glutamate in primary cultures of cortical neurons, whereas AC8 deletion did not produce a significant effect. AC1, but not AC8, contributes to intracellular cAMP production following NMDA receptor activation by glutamate in cultured cortical neurons. AC1 is involved in the dynamic modulation of cAMP-response element-binding protein activity in neuronal excitotoxicity. To explore the possible roles of AC1 in cell death in vivo, we studied neuronal excitotoxicity induced by an intracortical injection of NMDA. Cortical lesions induced by NMDA were significantly reduced in AC1 but not in AC8 knock-out mice. Our findings provide direct evidence that AC1 plays an important role in neuronal excitotoxicity and may serve as a therapeutic target for preventing excitotoxicity in stroke and neurodegenerative diseases.Neuronal death in stroke and other neurodegenerative diseases is mainly mediated by excitotoxicity. The central role of glutamate receptors in mediating excitotoxic neuronal death has been well established (1-5). Injury to the central nervous system triggers an abnormal release of glutamate and other excitatory amino acids that contributes significantly to the neurological outcome (5-8). The released glutamate causes an excessive activation of the NMDA 2 receptors, leading to calcium overload in neurons and subsequent neuronal death (1,3,6,9). The type of cell death in neuronal excitotoxicity seems to depend on the nature of the injury. Necrosis occurs after an acute insult, whereas apoptotic cell death is involved in propagation of the secondary injury (10 -12). Neuronal apoptosis induced by activation of NMDA receptors has been postulated to underlie the loss of neurons in many central nervous system disorders (13,14). Despite the initial promise of NMDA receptor antagonists and calcium channel blockers for the reduction of excitotoxic damage, clinical trials with these agents had to be abandoned because of toxic side-effects (15-17). The intervention of signaling events, which are downstream in excitotoxic cascade, might provide new strategies for the treatment of neuronal excitotoxicity. The cAMP signaling pathway has been shown to act downstream of NMDA receptor activation in synaptic plasticity (18 -22). The effect of the cAMP signaling pathway on cell survival depends on cell type and the specific type of cellular stress and may be influenced by cross-talk with other signal...

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“…The heptahelical 5-HTR 5 subtype is less characterized (21). 5-HTR 6 and 5-HTR 7 are linked to G s protein-mediated stimulation of adenylyl cyclase (22)(23)(24)(25)(26)(27)(28)(29).…”

Section: S Erotonin (5-hydroxytryptamine (5-ht))mentioning

confidence: 99%

The Serotoninergic Receptors of Human Dendritic Cells: Identification and Coupling to Cytokine Release

Idzko

Panther

Stratz

et al. 2004

The Journal of Immunology

192

203

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The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is stored at peripheral sites in mast cells and released from this peripheral source upon IgE cross-linking. In this study, we investigated the expression of serotoninergic receptors (5-HTR), the signaling pathway, and biological activity of 5-HT on human dendritic cells (DC), showing that immature and mature DC expressed mRNA for different serotoninergic receptors. Thereby, the mRNA of 5-HTR1B, 5-HTR1E, 5-HTR2A, 5-HTR2B, one splicing variant of the 5-HTR3, 5-HTR4, and 5-HTR7 receptors were detected. Immature DC preferentially expressed mRNA for the heptahelical 5-HTR1B, 5-HTR1E, and 5-HTR2B receptors, while mature DC mostly expressed 5-HTR4 and 5-HTR7. The mRNA expression level of the ligand-gated cation channel 5-HTR3 and the heptahelical 5-HTR2A did not significantly change during maturation. Isotype-selective receptor agonists allowed us to show that 5-HT stimulated 5-HTR3-dependent Ca2+ influx in immature and mature DC. Moreover, we revealed that 5-HTR1 and 5-HTR2 receptor stimulation induced intracellular Ca2+ mobilization via Gi/o proteins in immature, but not mature, DC. Activation of 5-HTR4 and 5-HTR7 induced cAMP elevation in mature DC. Functional studies indicated that activation of 5-HTR4 and 5-HTR7 enhanced the release of the cytokines IL-1β and IL-8, while reducing the secretion of IL-12 and TNF-α in mature DC. In summary, our study shows that 5-HT stimulated, in a maturation-dependent manner, different signaling pathways in DC. These data point to a role for 5-HT in regulating the immune response at peripheral sites.

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Stimulation of Type 1 and Type 8 Ca2+/Calmodulin-sensitive Adenylyl Cyclases by the Gs-coupled 5-Hydroxytryptamine Subtype 5-HT7AReceptor

Cited by 91 publications

References 56 publications

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

Genetic Evidence for Adenylyl Cyclase 1 as a Target for Preventing Neuronal Excitotoxicity Mediated by N-Methyl-D-aspartate Receptors

The Serotoninergic Receptors of Human Dendritic Cells: Identification and Coupling to Cytokine Release

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