Rho GTPases and Their Regulators in Addiction: A Focus on the Association of a β2-Chimaerin Polymorphism with Smoking

Abstract Tobacco addiction is a complex disorder that involves multiple molecular mechanisms and is influenced by genetic factors. Repeated exposure to nicotine induces the remodeling of synaptic connections, a process that contributes to the long-lasting nature of tobacco addiction. Rho GTPases are key regulators of synaptic structure and function and, therefore, these proteins have a potential role in nicotine addiction. In this chapter we will briefly describe some studies that identify genes encoding Rho GTPases and their regulators as candidate genes for smoking-related behaviors, with special focus on the CHN2 gene. The CHN2 gene encodes the β2-chimaerin, a member of the chimaerin family of GTPase activating proteins that selectively inactivates the GTPase Rac. Genetic studies suggest that nucleotide variants of the CHN2 gene may influence success in smoking cessation. In addition, work has identified a significant association of the rs186911567 polymorphism in the CHN2 gene with smoking in a Spanish population. We discuss how this polymorphism could alter β2-chimaerin function and the signaling pathways mediated by this protein that could influence smoking behavior.