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D2 dopamine receptor activation of potassium channels is selectively decoupled by Gα i ‐specific GoLoco motif peptides
Author(s) -
Webb Christina K.,
McCudden Christopher R.,
Willard Francis S.,
Kimple Randall J.,
Siderovski David P.,
Oxford Gerry S.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02997.x
Subject(s) - g protein coupled inwardly rectifying potassium channel , heterotrimeric g protein , g protein , microbiology and biotechnology , somatostatin , gi alpha subunit , chemistry , receptor , g protein coupled receptor , biology , biochemistry , neuroscience
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 Gα i1 , Gα i3 and, sometimes, Gα i2 subunits over Gα o subunits. This interaction prevents both spontaneous guanine nucleotide release and reassociation of Gα i ‐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.