Figure 2.

Mutations in the ERK/MAPK signaling pathway and related second messenger systems. The ERK/MAPK signaling pathway and related second messenger systems play a central role in neuronal and synaptic plasticity, affect regulation, and response to chronic stress. Mutations in genes related to these pathways could lead to reduced resilience and increased vulnerability. In a family with bipolar disorder and co-morbid anxiety spectrum disorders, we have identified potentially damaging mutations in genes related to these pathways. The genes encode proteins that are key regulators at several levels, from the cell membrane to the nucleus. IQUB and GOLGB1 are involved in G-protein coupled receptor recycling. FGGY, VRK2, GADD45A, and PLSCR proteins influence signal transduction through the ERK/MAPK messenger cascade. MESDC2 and JMJD1C influence CREB-regulated gene expression in the nucleus. Direct physical interaction has been reported between GADD45A and JMJD1C. These second messenger systems are also the target of lithium and valproic acid, which are commonly used to treat bipolar disorder. Green arrows indicate activating influences and red arrows indicate inhibiting influences.