The human 5‐HT<sub>7</sub> serotonin receptor splice variants: constitutive activity and inverse agonist effects

Krobert, Kurt A.; Levy, Finn Olav

doi:10.1038/sj.bjp.0704588

Cited by 96 publications

(103 citation statements)

References 34 publications

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“…It has been reported that several 5-HT receptors possess a constitutive, agonist-independent activity (Krobert and Levy, 2002). In the case of the 5-HT 7 receptor, we found that increased levels of 5-HT 7 cDNA (from 20 to 400 ng) resulted in a significant increase of SRE activity (from twofold to fivefold) under nonstimulated conditions (Fig.…”

Section: Resultssupporting

confidence: 58%

5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Kvachnina¹,

Liu²,

Dityatev³

et al. 2005

J. Neurosci.

180

220

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The neurotransmitter serotonin (5-HT) plays an important role in the regulation of multiple events in the CNS. We demonstrated recently a coupling between the 5-HT 4 receptor and the heterotrimeric G13-protein resulting in RhoA-dependent neurite retraction and cell rounding (Ponimaskin et al., 2002). In the present study, we identified G12 as an additional G-protein that can be activated by another member of serotonin receptors, the 5-HT 7 receptor. Expression of 5-HT 7 receptor induced constitutive and agonist-dependent activation of a serum response element-mediated gene transcription through G12-mediated activation of small GTPases. In NIH3T3 cells, activation of the 5-HT 7 receptor induced filopodia formation via a Cdc42-mediated pathway correlating with RhoA-dependent cell rounding. In mouse hippocampal neurons, activation of the endogenous 5-HT 7 receptors significantly increased neurite length, whereas stimulation of 5-HT 4 receptors led to a decrease in the length and number of neurites. These data demonstrate distinct roles for 5-HT 7 R/G12 and 5-HT 4 R/G13 signaling pathways in neurite outgrowth and retraction, suggesting that serotonin plays a prominent role in regulating the neuronal cytoarchitecture in addition to its classical role as neurotransmitter.

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Section: Resultssupporting

confidence: 58%

5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Kvachnina¹,

Liu²,

Dityatev³

et al. 2005

J. Neurosci.

180

220

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“…One of the characteristic features of 5-HT7 receptor is a high constitutive basal activity and results in homologous desensitization. Correspondingly, 5-HT7 receptors can be resensitized by a short exposure to antagonist, also known as reverse agonists, such as metergoline (MG) (24,25). We used this characteristic behavior of 5-HT7 to confirm that responses of mammary epithelial cells to 5-HT were consistent with these known properties of 5-HT7.…”

Section: Transmembrane Conductance Is Regulated By the 5-ht7mentioning

confidence: 90%

Biphasic Regulation of Mammary Epithelial Resistance by Serotonin through Activation of Multiple Pathways

Pai

Horseman

2008

Journal of Biological Chemistry

100

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Mammary gland homeostasis and the lactation-to-involution switch are regulated by serotonin (5-hydroxytryptamine (5-HT)). Mammary epithelial tight junctions are physiological targets of 5-HT, and their disruption marks an early stage of mammary gland involution. In these studies, we have identified signal transduction mechanism employed by 5-HT during regulation of mammary gland transepithelial resistance. Transepithelial electrical resistance and tight junction protein architecture were studied in cultures of MCF10A human mammary epithelial cells. Serotonin had biphasic effects on mammary epithelial resistance. At lower concentrations and earlier time points, 5-HT potentiated epithelial transmembrane resistance, whereas at higher concentrations and later time points, 5-HT decreased transepithelial electrical resistance and disrupted tight junctions. Both the early and delayed actions of 5-HT were mediated by the 5-HT7 receptor through activation of G s /cAMP. 5-HT induced the activities of both protein kinase A and p38 mitogen-activated protein kinase. Inhibition of p38 mitogen-activated protein kinase abrogated 5-HT-induced disruption of mammary epithelial tight junctions (the delayed effect). In contrast, inhibition of protein kinase A prevented the increased epithelial resistance in response to 5-HT (the transient effect). These studies imply an integrated set of mechanisms whereby transient, modest activation of 5-HT7 promotes tight junction integrity, and sustained 5-HT7 activation drives involution by disrupting tight junctions.The complex and specialized functions of mammary glands has evolved to meet the specific nutritional needs of the newborn. The rapid and extensive development of the mammary gland leading to establishment of the highly energy-consuming lactation stage is balanced by the massive tissue remodeling and disintegration of mammary epithelial tissue during the involution stage (1-3). Dysregulation of these events has severe consequences for maternal health and infant nutrition and health as well as from the practical perspective of dairy production.Under the influence of endocrine hormones like estrogen, progesterone, and prolactin, the mammary gland reaches the fully developed alveolar stage by the end of pregnancy. However, lactation (milk synthesis and secretion) is not established until parturition, characterized by a drop in systemic progesterone levels along with a surge in the levels of prolactin and glucocorticoids (4 -8). Isolation of the alveolar lumen from interstitial and vascular spaces by closure of tight junctions is a critical cellular event that regulates milk synthesis and secretion (9 -11). The importance of tight junction closure is displayed by the complex interplay between the endocrine hormones in regulating them and thus, in turn, regulating lactation (11-13).Each alveolar unit of a lactating mammary gland is independently regulated in an autocrine-paracrine manner through a feedback system of local factors (14 -16). Absence of a suckling stimulus results in accumu...

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“…Levy's group also extensively characterized the ability of the three isoforms to constitutively activate adenylyl cyclase and the inverse agonist properties of a series of antagonists. Again, 5-HT 7(a) , , and 5-HT 7(d) displayed similar profiles for both constitutive activity and inverse agonist responses (Krobert and Levy, 2002).…”

mentioning

confidence: 79%

Differential Agonist-Mediated Internalization of the Human 5-Hydroxytryptamine 7 Receptor Isoforms

Guthrie

Murray

Franklin

et al. 2005

J Pharmacol Exp Ther

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The human 5-hydroxytryptamine 7 (5-HT 7 ) serotonin receptor is a class A G-protein coupled receptor that has three isoforms, 5-HT 7(a) , , and 5-HT 7(d) , which are produced by alternative splicing. The 5-HT 7 receptors are expressed in discrete areas of the brain and in both vascular and gastrointestinal smooth muscle. Central nervous system 5-HT 7 receptors may play a role in mood and sleep disorders. 5-HT 7 receptors show high affinity for a number of antidepressants and typical and atypical antipsychotics. We report here that the human 5-HT 7(d) isoform expressed in human embryonic kidney (HEK) 293 cells exhibits a pattern of receptor trafficking in response to agonist that differ from 5-HT 7(a) or 5-HT 7(b) isoforms. We employed a modification of a live cell-labeling technique to demonstrate that surface 5-HT 7(d) receptors are constitutively internalized in the absence of agonist. This is in contrast to 5-HT 7(a) and 5-HT 7(b) isoforms, which do not show this profound agonistindependent internalization. Indeed, the 5-HT 7(d) isoform displays this internalization in the presence of a 5-HT 7 -specific antagonist. In addition, the human 5-HT 7(d) isoform shows a diminished efficacy in stimulation of cAMP-responsive reporter gene activity in transfected cells compared with 5-HT 7(a) or 5-HT 7(b) receptors expressed at comparable levels. Thus, the carboxy-terminal tail of 5-HT 7(d) , which is the longest among known human 5-HT 7 isoforms, may contain a motif that interacts with cellular transport mechanisms that is distinct from 5-HT 7(a) and 5-HT 7(b) .Serotonin (5-hydroxytryptamine; 5-HT) is a small molecule involved in a number of physiological and pathological processes. Fourteen subtypes of receptors and the serotonin transporter mediate these processes.The human 5-HT 7 receptor was cloned in 1993 (Bard et al., 1993). 5-HT 7 receptors are expressed in the central nervous system (thalamus, hypothalamus, limbic, and cortical regions), but also in peripheral tissues (vascular and gastrointestinal smooth muscle and certain leukocytes) . A variety of approaches has provided evidence that 5-HT 7 receptors may be involved in regulation of affect, body temperature, circadian rhythms and rapid eye movement sleep, primary sensory neuronal sensitivity, and relaxation of smooth muscle in a variety

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The human 5‐HT₇ serotonin receptor splice variants: constitutive activity and inverse agonist effects

Cited by 96 publications

References 34 publications

5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Biphasic Regulation of Mammary Epithelial Resistance by Serotonin through Activation of Multiple Pathways

Differential Agonist-Mediated Internalization of the Human 5-Hydroxytryptamine 7 Receptor Isoforms

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The human 5‐HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects

Cited by 96 publications

References 34 publications

5-HT7Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

5-HT7Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Biphasic Regulation of Mammary Epithelial Resistance by Serotonin through Activation of Multiple Pathways

Differential Agonist-Mediated Internalization of the Human 5-Hydroxytryptamine 7 Receptor Isoforms

Contact Info

Product

Resources

About

The human 5‐HT₇ serotonin receptor splice variants: constitutive activity and inverse agonist effects

5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology