D2 dopamine receptor activation of potassium channels is selectively decoupled by Gαi-specific GoLoco motif peptides

Christina K. Webb, Christopher R. McCudden, Francis S. Willard, Randall J. Kimple, David P. Siderovski, Gerry S. Oxford

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The GoLoco motif is a short polypeptide sequence found in G-protein signaling regulators such as regulator of G-protein signaling proteins type 12 and 14 and activator of G-protein signaling protein type 3. A unique property of the GoLoco motifs from these three proteins is their preferential interaction with guanosine diphosphate (GDP)-bound Gαi1, Gαi3 and, sometimes, Gαi2 subunits over Gαo subunits. This interaction prevents both spontaneous guanine nucleotide release and reassociation of Gαi-GDP with Gβγ. We utilized this property of the GoLoco motif to examine dopamine (D2 and D3) and somatostatin receptor coupling to G-protein-regulated inwardly rectifying potassium (GIRK) channels in mouse AtT20 cells. GoLoco motif peptides had no effect on either basal channel activity or the initial responses to agonists, suggesting that the GoLoco motif cannot disrupt pre-formed G-protein heterotrimers. GoLoco motif peptides did, however, interfere with human D2(short) receptor coupling to GIRK channels as demonstrated by the progressively diminished responses after repeated agonist application. This behavior is consistent with some form of compartmentalization of D2 receptors and GIRK channels such that Gβγ subunits, freed by local receptor activation and prevented from reforming a heterotrimeric complex, are not functionally constrained within the receptor - channel complex and thus are unable to exert a persistent activating effect. In contrast, GoLoco motif peptides had no effect on either D3 or somatostatin coupling to GIRK channels. Our results suggest that GoLoco motif-based peptides will be useful tools in examining the specificity of G-protein-coupled receptor-effector coupling.

Original languageEnglish
Pages (from-to)1408-1418
Number of pages11
JournalJournal of Neurochemistry
Volume92
Issue number6
DOIs
StatePublished - Mar 2005

Fingerprint

Dopamine D2 Receptors
Potassium Channels
Chemical activation
Peptides
GTP-Binding Proteins
Guanosine
Diphosphates
G Protein-Coupled Inwardly-Rectifying Potassium Channels
RGS Proteins
GTP-Binding Protein Regulators
Dopamine D3 Receptors
Inwardly Rectifying Potassium Channel
Somatostatin Receptors
Amino Acid Motifs
Guanine Nucleotides
Reforming reactions
G-Protein-Coupled Receptors
Somatostatin
Dopamine
Proteins

Keywords

  • G-proteins
  • Ion channels
  • Regulator of g-protein signaling proteins
  • Signal specificity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

D2 dopamine receptor activation of potassium channels is selectively decoupled by Gαi-specific GoLoco motif peptides. / Webb, Christina K.; McCudden, Christopher R.; Willard, Francis S.; Kimple, Randall J.; Siderovski, David P.; Oxford, Gerry S.

In: Journal of Neurochemistry, Vol. 92, No. 6, 03.2005, p. 1408-1418.

Research output: Contribution to journalArticle

Webb, Christina K. ; McCudden, Christopher R. ; Willard, Francis S. ; Kimple, Randall J. ; Siderovski, David P. ; Oxford, Gerry S. / D2 dopamine receptor activation of potassium channels is selectively decoupled by Gαi-specific GoLoco motif peptides. In: Journal of Neurochemistry. 2005 ; Vol. 92, No. 6. pp. 1408-1418.
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T1 - D2 dopamine receptor activation of potassium channels is selectively decoupled by Gαi-specific GoLoco motif peptides

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AB - The GoLoco motif is a short polypeptide sequence found in G-protein signaling regulators such as regulator of G-protein signaling proteins type 12 and 14 and activator of G-protein signaling protein type 3. A unique property of the GoLoco motifs from these three proteins is their preferential interaction with guanosine diphosphate (GDP)-bound Gαi1, Gαi3 and, sometimes, Gαi2 subunits over Gαo subunits. This interaction prevents both spontaneous guanine nucleotide release and reassociation of Gαi-GDP with Gβγ. We utilized this property of the GoLoco motif to examine dopamine (D2 and D3) and somatostatin receptor coupling to G-protein-regulated inwardly rectifying potassium (GIRK) channels in mouse AtT20 cells. GoLoco motif peptides had no effect on either basal channel activity or the initial responses to agonists, suggesting that the GoLoco motif cannot disrupt pre-formed G-protein heterotrimers. GoLoco motif peptides did, however, interfere with human D2(short) receptor coupling to GIRK channels as demonstrated by the progressively diminished responses after repeated agonist application. This behavior is consistent with some form of compartmentalization of D2 receptors and GIRK channels such that Gβγ subunits, freed by local receptor activation and prevented from reforming a heterotrimeric complex, are not functionally constrained within the receptor - channel complex and thus are unable to exert a persistent activating effect. In contrast, GoLoco motif peptides had no effect on either D3 or somatostatin coupling to GIRK channels. Our results suggest that GoLoco motif-based peptides will be useful tools in examining the specificity of G-protein-coupled receptor-effector coupling.

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