A bioactive peptide from the transmembrane 5 - intracellular loop 3 region of the human 5HT1a receptor

Hayataka, Kenneth; O’Connor, Mary Frances; Kinzler, Nancy; Weber, John T.; Parker, Keith K.

doi:10.1139/bcb-76-4-657

Cited by 7 publications

(4 citation statements)

References 19 publications

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“…The entire N-terminus [37] and C-terminus of i2 [38] of 5-HT 1A are thought to be sufficient to support G-protein coupling, but not signaling. On the other hand, the N-terminus [39] and C-terminus of i3 of 5-HT 1A [40], [41] seem to be essential for the G i signaling of 5-HT 1A . In fact, replacing the N-terminus of the i3 of the α 2 -adrenergic receptor with that of 5-HT 1A resulted in a chimera that signals like a 5-HT 1A receptor when stimulated by a α 2 -adrenergic receptor agonist [42].…”

Section: Discussionmentioning

confidence: 98%

Modifying Ligand-Induced and Constitutive Signaling of the Human 5-HT4 Receptor

Chang

Nguyen

et al. 2007

PLoS ONE

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G protein–coupled receptors (GPCRs) signal through a limited number of G-protein pathways and play crucial roles in many biological processes. Studies of their in vivo functions have been hampered by the molecular and functional diversity of GPCRs and the paucity of ligands with specific signaling effects. To better compare the effects of activating different G-protein signaling pathways through ligand-induced or constitutive signaling, we developed a new series of RASSLs (receptors activated solely by synthetic ligands) that activate different G-protein signaling pathways. These RASSLs are based on the human 5-HT4b receptor, a GPCR with high constitutive Gs signaling and strong ligand-induced G-protein activation of the Gs and Gs/q pathways. The first receptor in this series, 5-HT4-D100A or Rs1 (RASSL serotonin 1), is not activated by its endogenous agonist, serotonin, but is selectively activated by the small synthetic molecules GR113808, GR125487, and RO110-0235. All agonists potently induced Gs signaling, but only a few (e.g., zacopride) also induced signaling via the Gq pathway. Zacopride-induced Gq signaling was enhanced by replacing the C-terminus of Rs1 with the C-terminus of the human 5-HT2C receptor. Additional point mutations (D66A and D66N) blocked constitutive Gs signaling and lowered ligand-induced Gq signaling. Replacing the third intracellular loop of Rs1 with that of human 5-HT1A conferred ligand-mediated Gi signaling. This Gi-coupled RASSL, Rs1.3, exhibited no measurable signaling to the Gs or Gq pathway. These findings show that the signaling repertoire of Rs1 can be expanded and controlled by receptor engineering and drug selection.

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Section: Discussionmentioning

confidence: 98%

Modifying Ligand-Induced and Constitutive Signaling of the Human 5-HT4 Receptor

Chang

Nguyen

et al. 2007

PLoS ONE

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“…The following question arises: can coupling and activation characteristics be identified for the loop on a subregional basis? Our preliminary work at the N-terminal aspect of H5HT1a'a ic3 suggested to us that the techniques we use could be productive in addressing such a question [49, 50, 53]. Thus, we synthesized peptides of 10 residues each that progress from the N-terminus of ic2 to the C-terminus two amino acids at a time (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…In previous work [49, 50, 53, 54], we have demonstrated the utility of an agonist-based inhibition system associated with signal transduction parameters to study interactions of the receptor with its cognate G protein, Gi. In the current investigation we have presented further information about the H5HT1aR/Gi interface that should provide testable hypotheses anticipating the ultimate structural analysis of the receptor.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular Loop 2 Peptides of the Human 5HT1a Receptor are Differential Activators of Gi

Hall

Squires

Parker

2012

International Journal of Peptides

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Peptide mimics of intracellular loop 2 (ic2) of the human 5HT1a receptor have been studied with respect to their ability to inhibit agonist binding via interference with receptor-G-protein coupling. These peptides give shallow concentration-effect relationships. Additionally, these peptides have been studied with respect to their ability to trigger the signal transduction system of this Gi-coupled receptor. Two signaling parameters have been quantified: concentration of intracellular cAMP and changes in incorporation into the G protein of a stable analog of GTP. In both cases, peptide mimics near midloop of ic2 actually show agonist activity with efficacy falling off toward both loop termini near TM 3 and TM 4. Previous results have suggested that the loop region near the TM3/ic2 interface is primarily responsible for receptor-G-protein coupling, while the current result emphasizes the mid-ic2 loop region's ability to activate the G protein following initial coupling. A limited number of peptides from the receptor's TM5/ic3 loop vicinity were also studied regarding agonist inhibition and G-protein activation. These peptides provide additional evidence that the human 5HT1a receptor, TM5/ic3 loop region, is involved in both coupling and activation actions. Overall, these results provide further information about potential pharmacological intervention and drug development with respect to the human 5HT1a receptor/G-protein system. Finally, the structural evidence generated here provides testable models pending crystallization and X-ray analysis of the receptor.

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Extramembranous Regions in G Protein-Coupled Receptors: Cinderella in Receptor Biology?

Pal

Chattopadhyay

2019

J Membrane Biol

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A bioactive peptide from the transmembrane 5 - intracellular loop 3 region of the human 5HT1a receptor

Cited by 7 publications

References 19 publications

Modifying Ligand-Induced and Constitutive Signaling of the Human 5-HT4 Receptor

Modifying Ligand-Induced and Constitutive Signaling of the Human 5-HT4 Receptor

Intracellular Loop 2 Peptides of the Human 5HT1a Receptor are Differential Activators of Gi

Extramembranous Regions in G Protein-Coupled Receptors: Cinderella in Receptor Biology?

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