Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators
It has become evident that activation of heterotrimeric G-proteins by cytoplasmic proteins that are not G-protein-coupled receptors (GPCRs) plays a role in physiology and disease. Despite sharing the same biochemical guanine nucleotide exchange factor (GEF) activity as GPCRs in vitro, the mechanisms...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/65620 |
| _version_ | 1811235773653975040 |
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| author | Mikel Garcia-Marcos |
| author_facet | Mikel Garcia-Marcos |
| author_sort | Mikel Garcia-Marcos |
| collection | DOAJ |
| description | It has become evident that activation of heterotrimeric G-proteins by cytoplasmic proteins that are not G-protein-coupled receptors (GPCRs) plays a role in physiology and disease. Despite sharing the same biochemical guanine nucleotide exchange factor (GEF) activity as GPCRs in vitro, the mechanisms by which these cytoplasmic proteins trigger G-protein-dependent signaling in cells have not been elucidated. Heterotrimeric G-proteins can give rise to two active signaling species, Gα-GTP and dissociated Gβγ, with different downstream effectors, but how non-receptor GEFs affect the levels of these two species in cells is not known. Here, a systematic comparison of GPCRs and three unrelated non-receptor proteins with GEF activity in vitro (GIV/Girdin, AGS1/Dexras1, and Ric-8A) revealed high divergence in their contribution to generating Gα-GTP and free Gβγ in cells directly measured with live-cell biosensors. These findings demonstrate fundamental differences in how receptor and non-receptor G-protein activators promote signaling in cells despite sharing similar biochemical activities in vitro. |
| first_indexed | 2024-04-12T11:57:46Z |
| format | Article |
| id | doaj.art-25abbd51c01f487e9be3fa6413538c4e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T11:57:46Z |
| publishDate | 2021-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-25abbd51c01f487e9be3fa6413538c4e2022-12-22T03:33:57ZengeLife Sciences Publications LtdeLife2050-084X2021-03-011010.7554/eLife.65620Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activatorsMikel Garcia-Marcos0https://orcid.org/0000-0001-9513-4826Department of Biochemistry, Boston University School of Medicine, Boston, United StatesIt has become evident that activation of heterotrimeric G-proteins by cytoplasmic proteins that are not G-protein-coupled receptors (GPCRs) plays a role in physiology and disease. Despite sharing the same biochemical guanine nucleotide exchange factor (GEF) activity as GPCRs in vitro, the mechanisms by which these cytoplasmic proteins trigger G-protein-dependent signaling in cells have not been elucidated. Heterotrimeric G-proteins can give rise to two active signaling species, Gα-GTP and dissociated Gβγ, with different downstream effectors, but how non-receptor GEFs affect the levels of these two species in cells is not known. Here, a systematic comparison of GPCRs and three unrelated non-receptor proteins with GEF activity in vitro (GIV/Girdin, AGS1/Dexras1, and Ric-8A) revealed high divergence in their contribution to generating Gα-GTP and free Gβγ in cells directly measured with live-cell biosensors. These findings demonstrate fundamental differences in how receptor and non-receptor G-protein activators promote signaling in cells despite sharing similar biochemical activities in vitro.https://elifesciences.org/articles/65620G-protein-coupled receptor (GPCR)GTPaseGEFBRETGIVGirdin |
| spellingShingle | Mikel Garcia-Marcos Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators eLife G-protein-coupled receptor (GPCR) GTPase GEF BRET GIV Girdin |
| title | Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators |
| title_full | Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators |
| title_fullStr | Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators |
| title_full_unstemmed | Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators |
| title_short | Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators |
| title_sort | complementary biosensors reveal different g protein signaling modes triggered by gpcrs and non receptor activators |
| topic | G-protein-coupled receptor (GPCR) GTPase GEF BRET GIV Girdin |
| url | https://elifesciences.org/articles/65620 |
| work_keys_str_mv | AT mikelgarciamarcos complementarybiosensorsrevealdifferentgproteinsignalingmodestriggeredbygpcrsandnonreceptoractivators |