Mechanical Stretch Redefines Membrane Gαq-Calcium Signaling Complexes.

Muscle cells are routinely subjected to mechanical stretch but the impact of stretch on the organization of membrane domains is unknown. In this study, we characterize the effect of stretch on GPCR-Gαq protein signaling. Activation of this pathway leads to an increase in intracellular calcium. In muscle cells, GPCR-Gαq signals are enhanced when these proteins are localized in caveolae membrane domains whose curved structure can flatten with stretch. When we statically stretch rat aortic smooth muscle A10 cells by 1-5%, cellular calcium appears unperturbed as indicated by a calcium indicator. However, when we activate the bradykinin type 2 receptor (B2R)/Gαq pathway, we observe a loss in calcium that appears to be mediated through perturbations in calcium-activated stretch receptors. In contrast, if we apply oscillating stretch, calcium levels are enhanced. We tested whether the observed changes in B2R-Gαq calcium signals were caused by stretch-induced disruption of caveolae using a combination of silencing RNA technology and growth conditions. We find that stretch changes the ability of monoclonal caveolin antibodies to bind caveolae indicating a change in configuration of the domains. This change is seen by the inability of cells to survive stretch cycles when the level of caveolae is significantly reduced. Our studies show that the effect of calcium signals by mechanical stretch is mediated by the type of stretch and the amount of caveolae.

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