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

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 G alpha in membrane microdomains (such as lipid rafts) or the cytosol. Tubulin binds with nanomolar affinity to Gs alpha, Gi alpha 1 and Gq alpha ( but not other G alpha subunits) as well as G beta(1)gamma(2) subunits. G alpha subunits destabilize microtubules by stimulating tubulin's GTPase, while G beta gamma subunits promote microtubule stability. The same region on Gs alpha that binds adenylyl cyclase and G beta gamma also interacts with tubulin, suggesting that cytoskeletal proteins are novel G alpha effectors. Additionally, intracellular Gi alpha-GDP, in concert with other GTPase proteins and G beta gamma, 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. Copyright (C) 2009 S. Karger AG, Basel