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| Content Provider | Springer Nature Link |
|---|---|
| Author | Mutneja, Manpreet Berton, Frédérique Suen, Ka Fai Lüscher, Christian Slesinger, Paul A. |
| Copyright Year | 2004 |
| Abstract | The coupling of GABAB receptors to G-protein-gated inwardly rectifying potassium (GIRK) channels constitutes an important inhibitory pathway in the brain. Here, we examined the mechanism underlying desensitization of agonist-evoked currents carried by homomeric GIRK2 channels expressed in HEK-293T cells. The canonical GABAB receptor agonist baclofen produced GIRK2 currents that decayed by 57.3±1.4% after 60 s of stimulation, and then deactivated rapidly (time constant of 3.90±0.21 s) upon removal of agonist. Surface labeling studies revealed that GABAB receptors, in contrast to µ opioid receptors (MOR), did not internalize with a sustained stimulation for 10 min, excluding receptor redistribution as the primary mechanism for desensitization. Furthermore, heterologous desensitization was observed between GABAB receptors and MOR, implicating downstream proteins, such G-proteins or the GIRK channel. To investigate the G-protein turnover cycle, the non-hydrolyzable GTP analogue (GTPγS) was included in the intracellular solution and found to attenuate desensitization to 38.3±2.0%. The extent of desensitization was also reduced (45.3±1.3%) by coexpressing a mutant form of the Gαq G-protein subunit that has been designed to sequester endogenous RGS proteins. Finally, reconstitution of GABAB receptors with Gαo G-proteins rendered insensitive to RGS resulted in significantly less desensitization (28.5±3.2%). Taken together, our results demonstrate that endogenous levels of RGS proteins effectively enhance GABAB receptor-dependent desensitization of GIRK currents. |
| Starting Page | 61 |
| Ending Page | 73 |
| Page Count | 13 |
| File Format | |
| ISSN | 00316768 |
| Journal | Pflügers Archiv |
| Volume Number | 450 |
| Issue Number | 1 |
| e-ISSN | 14322013 |
| Language | English |
| Publisher | Springer-Verlag |
| Publisher Date | 2004-12-10 |
| Publisher Place | Berlin, Heidelberg |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Desensitization GABA GIRK Kir3 Potassium channels RGS proteins |
| Content Type | Text |
| Resource Type | Article |
| Subject | Physiology Physiology (medical) Clinical Biochemistry |
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