Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes

Saltzman, Alan; Morse, B; Whitman, Mary Maureen; Ivanshchenko, Yuri; Jaye, Michael; Felder, S

doi:10.1016/0006-291x(91)92105-s

Cited by 168 publications

(84 citation statements)

References 12 publications

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“…DNA Constructs and Transfection-The cDNA encoding the human 5HT2C receptor was generously supplied by Dr. Alan Saltzman (52). Mutations were introduced into the 5HT2C receptor using the QuikChange site-directed mutagenesis kit (Stratagene, La Jolla, CA) and confirmed by sequencing.…”

Section: Methodsmentioning

confidence: 99%

Conserved Helix 7 Tyrosine Acts as a Multistate Conformational Switch in the 5HT2C Receptor

Prioleau¹,

Visiers²,

Ebersole³

et al. 2002

Journal of Biological Chemistry

112

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Studies in many rhodopsin-like G-protein-coupled receptors are providing a general scheme of the structural processes underlying receptor activation. Microdomains in several receptors have been identified that appear to function as activation switches. However, evidence is emerging that these receptor proteins exist in multiple conformational states. To study the molecular control of this switching process, we investigated the function of a microdomain involving the conserved helix 7 tyrosine in the serotonin 5HT2C receptor. This tyrosine of the NPXXY motif was substituted for all naturally occurring amino acids. Three distinct constitutively active receptor phenotypes were found: moderate, high, and "locked-on" constitutive activity. In contrast to the activity of the other receptor mutants, the high basal signaling of the locked-on Y7.53N mutant was neither increased by agonists nor decreased by inverse agonists. The Y7.53F mutant was uncoupled. Computational modeling based on the rhodopsin crystal structure suggested that Y7.53 interacts with the conserved aromatic ring at position 7.60 in the recently identified helix 8 domain. This provided a basis for seeking revertant mutations to correct the defective function of the Y7.53F receptor. When the Y7.53F receptor was mutated at position 7.60, the wild-type phenotype was restored. These results suggest that Y7.53 and Y7.60 contribute to a common functional microdomain connecting helices 7 and 8 that influences the switching of the 5HT2C receptor among multiple active and inactive conformations.

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Section: Methodsmentioning

confidence: 99%

Conserved Helix 7 Tyrosine Acts as a Multistate Conformational Switch in the 5HT2C Receptor

Prioleau¹,

Visiers²,

Ebersole³

et al. 2002

Journal of Biological Chemistry

112

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“…By comparison, the homologies between the 5-HT2A or the 5-HT2C receptors from different species have homologies over 95 and 85%, respectively, and the rat and mouse 5-HT2B have 88% homology over the TM domains. Alignment of the TM region of 5-HT2 receptors places this receptor within the 5-HT2B subfamily [12], being slightly more divergent from 5-HT2A than from 5-HT2C; Homologies reach 71% with the human 5-HT2A receptor and 73% with the human 5-HT2C [13] and are around 70% for the 5-HT2A and 5-HT2C receptors of the same species. In addition, the human 5-HT2B genomic structure includes two introns ( Fig.…”

Section: Sequence Comparison Of the Human 5-ht2b Receptormentioning

confidence: 96%

The human serotonin 5‐HT2B receptor: Pharmacological link between 5‐HT2 and 5‐HT1D receptors

et al. 1994

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The human serotonin 5-HT2B receptor, isolated from a human liver cDNA library, was transfected in COS-I cells. Its pharmacological profile shows divergence with serotonin 5-HT2B receptors of other species. In particular, although strong correlation is observed between the human and the rat 5-HT2B receptor pharmacology, the correlation is almost as significant for the mouse 5-HT2B and the human 5-HT1D receptor agonists. The major sites of expression of its mRNA are in the human liver and kidney, with detectable expression in lung and heart. Therefore, this human 5-HT2B receptor could account for functions attributed to the peripheral 5-HTI D/5-HT2-1ike receptors, especially in the cardiovascular system. Thus, its detailed original pharmacology is of prime importance for therapeutic drug development.

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“…The human 5-HT,, aminoacid sequence displayed 79 and 82% overall sequence identity to the rat and mouse 5-HTZB receptors, respectively 12,311, 58% homology to the human 5-HT2A [32] and 51% to the human 5-HTZc receptor [32]. The homology within the membrane spanning regions was 91.5, 92, 71, and 73% for the rat and mouse SHT,,, the human 5-HT,, or SHT,, receptors, respectively.…”

Section: Protein Sequence Comparisonsmentioning

confidence: 98%

Cloning and functional characterization of the human 5‐HT_2B serotonin receptor

et al. 1994

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Recently, we have reported the cloning of the rat 5-HT,, receptor cDNA. This receptor is particularly interesting since it may be involved in diseases such as migraine. Here, we describe the isolation of a human 5-HT,, receptor clone from a cDNA library derived from SH-SYSY cells. Although the receptor sequence was only 80% homologous to the rat sequence, the exon-intron distribution was conserved between the two species. In the human body, the receptor mRNA was detected in most peripheral organs. Only low expression levels were found in the brain. After expression in HEK 293 cells, activation of the receptor stimulated the production of phosphatidylinositol. The pharmacology of this functional response correlated well with that of the rodent receptor.

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Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes

Cited by 168 publications

References 12 publications

Conserved Helix 7 Tyrosine Acts as a Multistate Conformational Switch in the 5HT2C Receptor

Conserved Helix 7 Tyrosine Acts as a Multistate Conformational Switch in the 5HT2C Receptor

The human serotonin 5‐HT2B receptor: Pharmacological link between 5‐HT2 and 5‐HT1D receptors

Cloning and functional characterization of the human 5‐HT_2B serotonin receptor

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Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes

Cited by 168 publications

References 12 publications

Conserved Helix 7 Tyrosine Acts as a Multistate Conformational Switch in the 5HT2C Receptor

Conserved Helix 7 Tyrosine Acts as a Multistate Conformational Switch in the 5HT2C Receptor

The human serotonin 5‐HT2B receptor: Pharmacological link between 5‐HT2 and 5‐HT1D receptors

Cloning and functional characterization of the human 5‐HT2B serotonin receptor

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Cloning and functional characterization of the human 5‐HT_2B serotonin receptor