The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons.
G proteins (Gα and Gβγ subtypes) drive adenylyl cyclase type 5 (AC5) synthesis of cAMP in striatal neurons, which is essential for motor coordination. KCTD5 directly interacts with Gβγ to delimit signaling events, yet downstream impact of KCTD5 in striatal circuits is not known. Here, generation of...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-04-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3003117 |
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| author | Douglas C Sloan Yini Liao Forest Ray Brian S Muntean |
| author_facet | Douglas C Sloan Yini Liao Forest Ray Brian S Muntean |
| author_sort | Douglas C Sloan |
| collection | DOAJ |
| description | G proteins (Gα and Gβγ subtypes) drive adenylyl cyclase type 5 (AC5) synthesis of cAMP in striatal neurons, which is essential for motor coordination. KCTD5 directly interacts with Gβγ to delimit signaling events, yet downstream impact of KCTD5 in striatal circuits is not known. Here, generation of a conditional Kctd5 knockout mouse identified that loss of striatal KCTD5 leads to a dystonic phenotype, coordination deficits, and skewed transitions between behavioral syllables. 2-photon imaging of a cAMP biosensor revealed electrically evoked dopaminergic responses were significantly augmented in the absence of KCTD5 in striatal circuits. cAMP sensitization was rescued in situ by expression of a Gβγ-scavenging nanobody and motor deficits were partially rescued in vivo by pharmacological antagonism of the indirect striatal cAMP pathway. Therefore, KCTD5 acts as a brake on cAMP signaling in striatal neurons important for tuning dopaminergic signaling and motor coordination. |
| format | Article |
| id | doaj-art-ab2dbc81a55b4869938ca111dd303684 |
| institution | OA Journals |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-ab2dbc81a55b4869938ca111dd3036842025-08-20T02:19:19ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852025-04-01234e300311710.1371/journal.pbio.3003117The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons.Douglas C SloanYini LiaoForest RayBrian S MunteanG proteins (Gα and Gβγ subtypes) drive adenylyl cyclase type 5 (AC5) synthesis of cAMP in striatal neurons, which is essential for motor coordination. KCTD5 directly interacts with Gβγ to delimit signaling events, yet downstream impact of KCTD5 in striatal circuits is not known. Here, generation of a conditional Kctd5 knockout mouse identified that loss of striatal KCTD5 leads to a dystonic phenotype, coordination deficits, and skewed transitions between behavioral syllables. 2-photon imaging of a cAMP biosensor revealed electrically evoked dopaminergic responses were significantly augmented in the absence of KCTD5 in striatal circuits. cAMP sensitization was rescued in situ by expression of a Gβγ-scavenging nanobody and motor deficits were partially rescued in vivo by pharmacological antagonism of the indirect striatal cAMP pathway. Therefore, KCTD5 acts as a brake on cAMP signaling in striatal neurons important for tuning dopaminergic signaling and motor coordination.https://doi.org/10.1371/journal.pbio.3003117 |
| spellingShingle | Douglas C Sloan Yini Liao Forest Ray Brian S Muntean The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons. PLoS Biology |
| title | The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons. |
| title_full | The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons. |
| title_fullStr | The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons. |
| title_full_unstemmed | The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons. |
| title_short | The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons. |
| title_sort | g protein modifier kctd5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons |
| url | https://doi.org/10.1371/journal.pbio.3003117 |
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