Trio and Kalirin as unique enactors of Rho/Rac spatiotemporal precision

Rac1 and RhoA are among the most widely studied small GTPases. The classic dogma surrounding their biology has largely focused on their activity as an "on/off switch" of sorts. However, the advent of more sophisticated techniques, such as genetically-encoded FRET-based sensors, has afforded the ability to delineate the spatiotemporal regulation of Rac1 and RhoA. As a result, there has been a shift from this simplistic global view to one incorporating the precision of spatiotemporal modularity. This review summarizes emerging data surrounding the roles of Rac1 and RhoA as cytoskeletal regulators and examines how these new data have led to a revision of the traditional dogma which placed Rac1 and RhoA in antagonistic pathways. This more recent evidence suggests that rather than absolute activity levels, it is the tight spatiotemporal regulation of Rac1 and RhoA across multiple roles, from oppositional to complementary, that is necessary to execute coordinated cytoskeletal processes affecting cell structure, function, and migration. We focus on how Kalirin and Trio, as dual GEFs that target Rac1 and RhoA, are uniquely designed to provide the spatiotemporally-precise shifts in Rac/Rho balance which mediate changes in neuronal structure and function, particularly by way of cytoskeletal rearrangements. Finally, we review how alterations in Trio and/or Kalirin function are associated with cellular abnormalities and neuropsychiatric disease.