Cloning of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic loop

Kohen, Ruth; Fashingbauer, Lucy A.; Heidmann, Doris; Guthrie, Chris R.; Hamblin, Mark W.

doi:10.1016/s0169-328x(01)00090-0

Cited by 99 publications

(73 citation statements)

References 27 publications

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“…Functional characteristics of the HA-modified 5-HT 6 receptor was evaluated using a luciferase-based cAMP assay (Kohen et al, 2001). PC12 cells were seeded onto 24-well plates, and grown to 50% confluence in Dulbecco's modified Eagle's media supplemented with 12% fetal calf serum and ampicillin.…”

Section: Confirmation Of Transgene Functionmentioning

confidence: 99%

Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning

Mitchell

Sexton

Neumaier

2006

Neuropsychopharmacol

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A number of studies have shown that systemic 5-HT 6 receptor antagonists can improve learning and memory, but the mechanism for these observations is not known. As striatum normally expresses 5-HT 6 receptors abundantly and is important in consolidating stimulusresponse learning, we used targeted gene delivery to further increase the expression of 5-HT 6 receptors in rat striatum and then examined learning. Increased 5-HT 6 expression had no effect on performance in the Morris water maze, a hippocampal-dependent learning paradigm, and did not alter the latency to approach or consume sucrose tablets. However, rats with increased 5-HT 6 expression failed to acquire a reward-based instrumental learning task, a striatum-dependent learning model, during 3 days of successive sessions as compared to sham surgery or GFP-expressing control rats. This behavioral deficit was observed in rats overexpressing 5-HT 6 receptors in the dorsomedial striatum, but not in rats with increased dorsocentral striatal expression. The 5-HT 6 receptor-associated deficit was reversed by administration of a 5-HT 6 antagonist, SB-258585, before each training session. When animals learned the instrumental learning task before gene transfer, increased 5-HT 6 receptor expression had no effect on long-term recall or performance of the task or on extinction of operant responding. Thus, 5-HT 6 receptor activity in rat striatum disrupts acquisition of new instrumental learning but does not impair memory or performance of reward-motivated behavior once established.

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Section: Confirmation Of Transgene Functionmentioning

confidence: 99%

Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning

Mitchell

Sexton

Neumaier

2006

Neuropsychopharmacol

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“…The 5-HT 6 receptor is a Gs-coupled receptor that activates cAMP formation on agonist stimulation in several recombinant systems (4)(5)(6) as well as in native systems, such as primary neurons (7) and pig caudate membranes (8). In addition to its coupling to G proteins, the 5-HT 6 receptor interacts with the Src family tyrosine kinase Fyn (9), the Jun activation domain-binding protein 1 (10), and the microtubule-associated protein Map1b (11).…”

mentioning

confidence: 99%

“…Constitutive activity of 5-HT 6 receptor was also established at Gs signaling in recombinant cells overexpressing WT or mutant receptors (5,6), but the underlying mechanism remains to be established. In light of recent evidence indicating that G protein-coupled receptor (GPCR) constitutive activity can be modulated by G protein-coupled receptor-interacting proteins (GIPs) (15), we focused on neurofibromin, another 5-HT 6 receptor partner known to be involved in adenylyl cyclase activation by various GPCRs (12,16).…”

mentioning

confidence: 99%

Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity

Nadim

Chaumont‐Dubel

Madouri

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT 6 ) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the RasGTPase activating protein (Ras-GAP) neurofibromin, a 5-HT 6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT 6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT 6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT 6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1 +/− mice compared with WT mice. Moreover, systemic administration of a 5-HT 6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1 +/− mice. Collectively, these findings suggest that disrupting 5-HT 6 receptor-neurofibromin interaction prevents agonist-independent 5-HT 6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients.5-HT 6 receptor | constitutive activity | G protein-coupled receptor | neurofibromin | neurofibromatosis type 1

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“…The compound 6b was also evaluated in 5-HT 6 reporter gene cell-based functional assay 43,44 . The tested compound 6b has shown antagonistic activity by inhibiting the 5-HT-stimulated cAMP accumulation, with a K b value of 4.92 ± 0.13 nM and IC 50 value of 548.2 ± 3.6 nM.…”

Section: Structure-activity Relationship (Sar)mentioning

confidence: 99%

Synthesis and biological evaluation of novel N₁-phenylsulphonyl indole derivatives as potent and selective 5-HT₆R ligands for the treatment of cognitive disorders

Nirogi

Bandyala

Gangadasari

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 1-[3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole and 1-[3-(4-ethyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole derivatives were designed and synthesized as 5-HT 6 receptor (5-HT 6 R) ligands. The lead compound 1-[4-methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-1H-indole dihydrochloride (6b), in this series, has shown potent in vitro binding affinity, selectivity, good pharmacokinetics (PK) profile and activity in the animal models of cognition.

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Cloning of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic loop

Cited by 99 publications

References 27 publications

Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning

Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning

Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity

Synthesis and biological evaluation of novel N₁-phenylsulphonyl indole derivatives as potent and selective 5-HT₆R ligands for the treatment of cognitive disorders

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Cloning of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic loop

Cited by 99 publications

References 27 publications

Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning

Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning

Physical interaction between neurofibromin and serotonin 5-HT 6 receptor promotes receptor constitutive activity

Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

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Product

Resources

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Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity

Synthesis and biological evaluation of novel N₁-phenylsulphonyl indole derivatives as potent and selective 5-HT₆R ligands for the treatment of cognitive disorders