Abstract
We examined the role of G proteins in modulating the response of living cells to receptor activation. The response of an effector, phospholipase C-β to M3 muscarinic receptor activation was measured using sensors that detect the generation of inositol triphosphate or diacylglycerol. The recently discovered translocation of Gβγ from plasma membrane to endomembranes on receptor activation attenuated this response. A FRET based G protein sensor suggested that in contrast to translocating Gβγ, non-translocating Gβγ subunits do not dissociate from the αq subunit on receptor activation leading to prolonged retention of the heterotrimer state and an accentuated response. M3 receptors with tethered αq induced differential responses to receptor activation in cells with or without an endogenous translocation capable γ subunit. G protein heterotrimer dissociation and βγ translocation are thus unanticipated modulators of the intensity of a cell's response to an extracellular signal.
Highlights
G proteins are the major modulators of cellular responses to external signals in mammalian cells [1,2]
pleckstrin homology (PH)-mCh translocates from the plasma membrane to the cytosol on phospholipases C b isozymes (PLCs) b activation and the magnitude of PH-mCh translocation is indicative of extent of PIP2 breakdown on the PM
We show here that the ability of G protein c subunit types to translocate away from the plasma membrane on receptor activation controls sensitivity of response
Summary
G proteins are the major modulators of cellular responses to external signals in mammalian cells [1,2]. There is limited information on the role that G proteins play in directly regulating the sensitivity of a cell’s response to an external stimulus in living cells. The kinetics of the rod photoreceptor G protein, Gt, mediated phototransduction activity has been examined in highly specialized rod photoreceptor cells which are amenable to such studies [5]. Little is known about such processes with regard to the large families of G protein subunits that are expressed widely in all mammalian cell types. We have used imaging methods to examine whether mechanisms at the level of the G protein subunits control the intensity of the response to receptor activation in intact living cells
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