The SEK-1 p38 MAP Kinase Pathway Regulates Gq Signaling in C. elegans

Abstract

Gq is a heterotrimeric G protein that is widely expressed in neurons and regulates neuronal activity. To identify pathways regulating neuronal Gq signaling we performed a forward genetic screen in Caenorhabditis elegans for suppressors of activated Gq. One of the suppressors is an allele of sek-1, which encodes a mitogen-activated protein kinase kinase (MAPKK) in the p38 MAPK pathway. We report that sek-1 mutants have a slow locomotion rate. We show that sek-1 acts in cholinergic neurons to regulate both locomotion and Gq signaling. Furthermore, we show that sek-1 acts in mature neurons to regulate locomotion. We used genetic and behavioral approaches to demonstrate that other components of the p38 MAPK pathway also play a positive role in regulating locomotion and Gq signaling. There are two pathways downstream of Gq in C. elegans (PLCβ/EGL-8 and UNC-73/Trio) and we show that sek-1 acts in the UNC-73/Trio pathway. Finally, we find that mutants in the sek-1 p38 MAPK pathway partially suppress an activated mutant of the sodium leak channel NCA-1/NALCN, a downstream target of Gq signaling. Our results suggest that the sek-1 p38 pathway may modulate the output of Gq signaling through NCA-1.