Epigenetic Effects Induced by Methamphetamine and Methamphetamine-Dependent Oxidative Stress

Figure 7

An overview of canonical DA receptor signaling. During physiologic DA stimulation, AC activity is balanced by the excitatory and inhibitory effects of DRD1 and DRD2, respectively. Thus, there is a physiologic downregulation of cAMP and PKA activation. PKA has a broad array of targets such as the DA- and cAMP-regulated phosphoprotein (DARPP-32), voltage-gated ion channels, and GLUT receptors. PKA phosphorylates DARPP-32 at Thr34 (P-T34), but other proteins, such as cyclin-dependent kinase 5 (CDK5), counterbalance such an effect by phosphorylating DARPP-32 at a different site (P-T75). Thus, DARPP-32 can activate phosphatase protein 1 (PP1), which can surveil phosphorylation levels of all PKA targets. Likewise, canonical stimulation of DRD2, which are coupled with PLC, generates normal levels of inositol 1,4,5 trisphosphate (IP3) which induces Ca2+ release from the endoplasmic reticulum. Since ion channels and GLUT receptors are properly functioning, intracellular Ca2+ can be efficiently mobilized.