The MAPK/ERK pathway plays a critical role in regulating neuronal activity in C. elegans. The regulation of MAP3K Raf and its targets have been well-studied in growth and development, as unregulated ERK signaling causes cancer.However, the regulation of Raf activity in neurons and how ERK signaling affects neuronal activity are not understood.Overexpression of activated LIN-45/Raf (Raf*) in neurons results in loopy locomotion. While performing a forward genetic screen for suppressors of Raf*, we identified components that (1) affect the activity of Raf and (2) are downstream targets that directly affect neuronal activity. Loss of Kinase Suppressor of Ras 1 (KSR-1) suppresses the loopy locomotion of Raf* expressing worms. KSR-1 is known to heterodimerize with Raf, and this is critical for Raf function. Our experiments demonstrate that even Raf* requires KSR-1 in neurons to promote signaling. We also identified auxiliary subunits of the voltage sensitive cation channel NCA/NALCN as suppressors of Raf*. We found Raf* and the NCA mutant
nlf-1 were mutually suppressing, as
nlf-1 mutants exhibit a distinct "fainting" behavior that is suppressed by Raf*. We explored by what mechanism Raf* suppresses fainting, either by enhancing impaired NCA function or via upregulation of neuronal activity via a separate pathway. As certain tumors are electrically active tissues that hijack neuronal signaling pathways to promote cancerous cell growth, these studies will relate to both neurobiology and cancer biology.