Environmental toxins, such as the herbicide paraquat, can cause damage to cells by inducing oxidative stress. 4-hydroxynonenal (4HNE) is the major lipid peroxidation product of oxidative stress and is highly reactive toward protein cysteine residues. RGS4 is a member of the Regulator of G protein signaling (RGS) protein family, and contains a cysteine residue (Cys148) that is sensitive to covalent modification, which irreversibly inhibits its function. RGS proteins are signaling checkpoints downstream of G protein coupled receptor (GPCR) activation and are critical for regulating the magnitude and duration of GPCR-mediated cell signaling events. We hypothesize that this sensitive site on RGS4 (Cys148) is modified during oxidative stress by 4HNE, thus inhibiting RGS4 function. As alterations in GPCR signaling and RGS protein function are evident in neurodegenerative diseases such as Parkinson’s, this proposal seeks to define the role of oxidative stress and 4HNE in RGS4 inhibition and subsequent cellular signaling dysfunction.