A bifunctional Gαi/Gαs modulatory peptide that attenuates adenylyl cyclase activity

Christopher A. Johnston; J. Kevin Ramer; Rainer Blaesius; Zoey Fredericks; Val J. Watts; David P. Siderovski

doi:10.1016/j.febslet.2005.09.059

A bifunctional Gα_i/Gα_s modulatory peptide that attenuates adenylyl cyclase activity

Christopher A. Johnston, J. Kevin Ramer, Rainer Blaesius, Zoey Fredericks, Val J. Watts, David P. Siderovski

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Signaling via G-protein coupled receptors is initiated by receptor-catalyzed nucleotide exchange on Gα subunits normally bound to GDP and Gβγ. Activated Gα • GTP then regulates effectors such as adenylyl cyclase. Except for Gβγ, no known regulators bind the adenylyl cyclase-stimulatory subunit Gα_s in its GDP-bound state. We recently described a peptide, KB-752, that binds and enhances the nucleotide exchange rate of the adenylyl cyclase-inhibitory subunit Gα_i. Herein, we report that KB-752 binds Gα_s • GDP yet slows its rate of nucleotide exchange. KB-752 inhibits GTPγS-stimulated adenylyl cyclase activity in cell membranes, reflecting its opposing effects on nucleotide exchange by Gα_i and Gα_s.

Original language	English
Pages (from-to)	5746-5750
Number of pages	5
Journal	FEBS Letters
Volume	579
Issue number	25
DOIs	https://doi.org/10.1016/j.febslet.2005.09.059
State	Published - 24 Oct 2005

Keywords

Adenylyl cyclase
Biosensors
G-proteins
Phage display
Signal transduction
Surface plasmon resonance

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10.1016/j.febslet.2005.09.059

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title = "A bifunctional Gαi/Gαs modulatory peptide that attenuates adenylyl cyclase activity",

abstract = "Signaling via G-protein coupled receptors is initiated by receptor-catalyzed nucleotide exchange on Gα subunits normally bound to GDP and Gβγ. Activated Gα • GTP then regulates effectors such as adenylyl cyclase. Except for Gβγ, no known regulators bind the adenylyl cyclase-stimulatory subunit Gαs in its GDP-bound state. We recently described a peptide, KB-752, that binds and enhances the nucleotide exchange rate of the adenylyl cyclase-inhibitory subunit Gαi. Herein, we report that KB-752 binds Gαs • GDP yet slows its rate of nucleotide exchange. KB-752 inhibits GTPγS-stimulated adenylyl cyclase activity in cell membranes, reflecting its opposing effects on nucleotide exchange by Gαi and Gαs.",

keywords = "Adenylyl cyclase, Biosensors, G-proteins, Phage display, Signal transduction, Surface plasmon resonance",

author = "Johnston, {Christopher A.} and Ramer, {J. Kevin} and Rainer Blaesius and Zoey Fredericks and Watts, {Val J.} and Siderovski, {David P.}",

note = "Funding Information: We thank Chau H. Nguyen (Purdue Univ.) for technical assistance and Dr. Francis Willard (UNC) for design and first proof-of-concept data for the FITC-KB-752 peptide as well as critical appraisal of this manuscript. This work was supported by NIH Grants R01 GM062338 and P01 GM065533 to D.P.S. and R01 MH060397 to V.J.W.",

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doi = "10.1016/j.febslet.2005.09.059",

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AU - Johnston, Christopher A.

AU - Ramer, J. Kevin

AU - Blaesius, Rainer

AU - Fredericks, Zoey

AU - Watts, Val J.

AU - Siderovski, David P.

N1 - Funding Information: We thank Chau H. Nguyen (Purdue Univ.) for technical assistance and Dr. Francis Willard (UNC) for design and first proof-of-concept data for the FITC-KB-752 peptide as well as critical appraisal of this manuscript. This work was supported by NIH Grants R01 GM062338 and P01 GM065533 to D.P.S. and R01 MH060397 to V.J.W.

PY - 2005/10/24

Y1 - 2005/10/24

N2 - Signaling via G-protein coupled receptors is initiated by receptor-catalyzed nucleotide exchange on Gα subunits normally bound to GDP and Gβγ. Activated Gα • GTP then regulates effectors such as adenylyl cyclase. Except for Gβγ, no known regulators bind the adenylyl cyclase-stimulatory subunit Gαs in its GDP-bound state. We recently described a peptide, KB-752, that binds and enhances the nucleotide exchange rate of the adenylyl cyclase-inhibitory subunit Gαi. Herein, we report that KB-752 binds Gαs • GDP yet slows its rate of nucleotide exchange. KB-752 inhibits GTPγS-stimulated adenylyl cyclase activity in cell membranes, reflecting its opposing effects on nucleotide exchange by Gαi and Gαs.

AB - Signaling via G-protein coupled receptors is initiated by receptor-catalyzed nucleotide exchange on Gα subunits normally bound to GDP and Gβγ. Activated Gα • GTP then regulates effectors such as adenylyl cyclase. Except for Gβγ, no known regulators bind the adenylyl cyclase-stimulatory subunit Gαs in its GDP-bound state. We recently described a peptide, KB-752, that binds and enhances the nucleotide exchange rate of the adenylyl cyclase-inhibitory subunit Gαi. Herein, we report that KB-752 binds Gαs • GDP yet slows its rate of nucleotide exchange. KB-752 inhibits GTPγS-stimulated adenylyl cyclase activity in cell membranes, reflecting its opposing effects on nucleotide exchange by Gαi and Gαs.

KW - Adenylyl cyclase

KW - Biosensors

KW - G-proteins

KW - Phage display

KW - Signal transduction

KW - Surface plasmon resonance

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JO - FEBS Letters

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ER -

A bifunctional Gα_i/Gα_s modulatory peptide that attenuates adenylyl cyclase activity

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