Local membrane charge regulates β<sub>2</sub> adrenergic receptor coupling to G<sub>i3</sub>.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31110175.
- Also identified by DOI 10.1038/s41467-019-10108-0 and PMC identifier 6527575.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The β<sub>2</sub> adrenergic receptor (β<sub>2</sub>AR) signals through both G<sub>s</sub> and G<sub>i</sub> in cardiac myocytes, and the G<sub>i</sub> pathway counteracts the G<sub>s</sub> pathway. However, G<sub>i</sub> coupling is much less efficient than G<sub>s</sub> coupling in most cell-based and biochemical assays, making it difficult to study β<sub>2</sub>AR-G<sub>i</sub> interactions. Here we investigate the role of phospholipid composition on G<sub>s</sub> and G<sub>i</sub> coupling. While negatively charged phospholipids are known to enhance agonist affinity and stabilize an active state of the β<sub>2</sub>AR, we find that they impair coupling to G<sub>i3</sub> and facilitate coupling to G<sub>s</sub>. Positively charged Ca<sup>2+</sup> and Mg<sup>2+</sup>, known to interact with the negative charge on phospholipids, facilitates G<sub>i3</sub> coupling. Mutational analysis suggests that Ca<sup>2+</sup> coordinates an interaction between phospholipid and the negatively charged EDGE motif on the amino terminal helix of G<sub>i3</sub>. Taken together, our observations suggest that local membrane charge modulates the interaction between β<sub>2</sub>AR and competing G protein subtypes.
Medical subject headings
- Cell Membrane
- GTP-Binding Protein alpha Subunits, Gi-Go
- Membrane Lipids
- Receptors, Adrenergic, beta-2