The Role of DARPP-32, an Intracellular Signaling Molecule, in the Actions of the Nerve Agent Sarin

Abstract

Abstract : We investigated the role of DARPP-32 in mediating changes in phosphorylation after sarin exposure. Wild type mice and mice bearing a targeted disruption of the gene for DARPP-32 were exposed to sarin; levels of brain phosphoproteins were measured. Mice receiving 1.0 x LD50 dose of sarin displayed motor convulsions. No significant change in phosphorylation level of T75 DARPP-32 was observed in brains of wild type mice. Also, no significant changes in phosphorylation were observed in the brains of wild type or DARPP-32 knockout mice after 0.5 x LD50 sarin. At a sarin dose of 1.0 x LD50 a significant increase in CREB phosphorylation was observed. One difference was noted in brain phosphorylation between wild type and DARPP-32 knockout mice. The presence of DARPP-32 significantly affected the ability of sarin to alter phosphorylation of the AMPA receptor GluR1 at S831. An increase in phosphorylation measured in wild type mouse brain after sarin was significantly attenuated in the brain of DARPP-32 knockout mice, indicating that DARPP-32 may modulate the extent to which S831 responses are induced by sarin. The results of this study do not support the hypothesis that changes in phosphorylation levels of T75 DARPP-32 are necessary for phosphorylation changes observed in brain after a 1.0 x LD50 dose of sarin.