Bibliographic Details
| Title: |
Mechano-sensitivity of β2-adrenoceptors enhances constitutive activation of cAMP generation that is inhibited by inverse agonists. |
| Authors: |
Cullum, Sean A., Platt, Simon, Dale, Natasha, Isaac, Oliver C., Wragg, Edward S., Soave, Mark, Veprintsev, Dmitry B., Woolard, Jeanette, Kilpatrick, Laura E., Hill, Stephen J. |
| Source: |
Communications Biology; 4/5/2024, Vol. 7 Issue 1, p1-16, 16p |
| Subject Terms: |
G protein coupled receptors, CELL receptors, SITE-specific mutagenesis |
| Abstract: |
The concept of agonist-independent signalling that can be attenuated by inverse agonists is a fundamental element of the cubic ternary complex model of G protein-coupled receptor (GPCR) activation. This model shows how a GPCR can exist in two conformational states in the absence of ligands; an inactive R state and an active R* state that differ in their affinities for agonists, inverse agonists, and G-protein alpha subunits. The proportion of R* receptors that exist in the absence of agonists determines the level of constitutive receptor activity. In this study we demonstrate that mechanical stimulation can induce β2-adrenoceptor agonist-independent Gs-mediated cAMP signalling that is sensitive to inhibition by inverse agonists such as ICI-118551 and propranolol. The size of the mechano-sensitive response is dependent on the cell surface receptor expression level in HEK293G cells, is still observed in a ligand-binding deficient D113A mutant β2-adrenoceptor and can be attenuated by site-directed mutagenesis of the extracellular N-glycosylation sites on the N-terminus and second extracellular loop of the β2-adrenoceptor. Similar mechano-sensitive agonist-independent responses are observed in HEK293G cells overexpressing the A2A-adenosine receptor. These data provide new insights into how agonist-independent constitutive receptor activity can be enhanced by mechanical stimulation and regulated by inverse agonists. Use of a cAMP biosensor to study real-time mechano-sensitive enhancement of β2-adrenoceptor constitutive activity and its inhibition by β2-inverse agonists in HEK 293 cells. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
