Endogenous RGS proteins enhance acute desensitization of GABAB receptor-activated GIRK currents in HEK-293T cells

Manpreet Mutneja, Frédérique Berton, Ka Fai Suen, Christian Lüscher, Paul A. Slesinger

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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.

Original languageEnglish
Pages (from-to)61-73
Number of pages13
JournalPflugers Archiv European Journal of Physiology
Issue number1
StatePublished - Apr 2005
Externally publishedYes


  • Desensitization
  • GABA
  • GIRK
  • Kir3
  • Potassium channels
  • RGS proteins


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