Heterotrimeric G-Proteins Interact Directly with Cytoskeletal Components to Modify Microtubule-Dependent Cellular Processes

Abstract

A large percentage of current drugs target G-protein-coupled receptors, which couple to well-known signaling pathways involving cAMP or calcium. G-proteins themselves may subserve a second messenger function. Here, we review the role of tubulin and microtubules in directly mediating effects of heterotrimeric G-proteins on neuronal outgrowth, shape and differentiation. G-protein-tubulin interactions appear to be regulated by neurotransmitter activity, and, in turn, regulate the location of Gα in membrane microdomains (such as lipid rafts) or the cytosol. Tubulin binds with nanomolar affinity to Gsα, Giα1 and Gqα (but not other Gα subunits) as well as Gβ₁γ₂ subunits. Gα subunits destabilize microtubules by stimulating tubulin’s GTPase, while Gβγ subunits promote microtubule stability. The same region on Gsα that binds adenylyl cyclase and Gβγ also interacts with tubulin, suggesting that cytoskeletal proteins are novel Gα effectors. Additionally, intracellular Giα-GDP, in concert with other GTPase proteins and Gβγ, regulates the position of the mitotic spindle in mitosis. Thus, G-protein activation modulates cell growth and differentiation by directly altering microtubule stability. Further studies are needed to fully establish a structural mechanism of this interaction and its role in synaptic plasticity.

Ric-8A and Giα Recruit LGN, NuMA, and Dynein to the Cell Cortex To Help Orient the Mitotic Spindle

“…Astral microtubules that interact with the cell cortex may either deliver a signal or provide a direct delivery route for G␣ i via microtubule-based transport (15). G␣ i -GTP is known to bind microtubules while G␣ i -GDP does not (7). In Drosophila it has been proposed that Ric-8 might promote the lipid modification of G␣ i or even negatively regulate the removal of G␣ i from the cell cortex (36); however, in HeLa cells these mechanisms seem unlikely.…”

WDR36 acts as a scaffold protein tethering a G-protein-coupled receptor, Gαq and phospholipase Cβ in a signalling complex

“…However, WDR36 did not regulate TPb-mediated cAMP generation. Gas is known to internalize whereas Gaq stays at the plasma membrane following GPCR activation (Dave et al, 2009;Philip et al, 2007). By contrast, both Gas and Gaq were reported to localize with their receptors on tubular recycling endosomes (Scarselli and Donaldson, 2009).…”

The Expanding Roles of GβγSubunits in G Protein–Coupled Receptor Signaling and Drug Action

“…Among the myriad of cytoskeletal structural elements, the microtubule network plays roles in many different cellular processes [reviewed in Dave et al (2009) and Gundersen and Cook (1999)], including cell division, vesicle release, and signal transduction (Dong et al, 2000). Microtubules form a cylinder of heterodimeric tubulin subunits (a and b) that can bind GTP.…”