The Protein Arginine Methyltransferase PRMT-5 Regulates SER-2 Tyramine Receptor-Mediated Behaviors inCaenorhabditis elegans

Abstract

G protein-coupled receptors are 7-pass transmembrane receptors that couple to heterotrimeric G proteins to mediate cellular responses to a diverse array of stimuli. Understanding the mechanisms that regulate G protein-coupled receptors is crucial to manipulating their signaling for therapeutic benefit. One key regulatory mechanism that contributes to the functional diversity of many signaling proteins is post-translational modification. Whereas phosphorylation remains the best studied of such modifications, arginine methylation by protein arginine methyltransferases is emerging as a key regulator of protein function. We previously published the first functional evidence that arginine methylation of G protein-coupled receptors modulates their signaling. We report here a third receptor that is regulated by arginine methylation, the Caenorhabditis elegans SER-2 tyramine receptor. We show that arginines within a putative methylation motif in the third intracellular loop of SER-2 are methylated by PRMT5 in vitro. Our data also suggest that this modification enhances SER-2 signaling in vivo to modulate animal behavior. The identification of a third G protein-coupled receptor to be functionally regulated by arginine methylation suggests that this post-translational modification may be utilized to regulate signaling through a broad array of G protein-coupled receptors.

Assessing effects of germline exposure to environmental toxicants by high-throughput screening in C. elegans

“…SPO-11 is the topoisomerase-like conserved protein that catalyzes meiotic DSBs so that the elevated levels of DSB formation observed in DBP exposed worms may be due in part to deregulation of spo-11 expression. prmt-5 encodes for the ortholog of human PRMT5, a protein arginine methyltransferase involved in the post-translational modification of a variety of proteins including histones and G protein-coupled receptors, thereby regulating transcription and signaling [91]. Interestingly, PRMT5 has been proposed to regulate the target gene specificity of p53 in mammals [74] and to negatively regulate apoptotic signaling in response to DNA damage in C .…”

Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans

“…https://doi.org/10.1371/journal.pgen.1008529.g005 by a two-tailed unpaired t-test), an arginine methyltransferase involved in the modification of histones and receptors involved in signaling and transcription regulation, that could lead to altered gene expression or chromosome structure resulting in the observed increased levels of DSBs [56] (Fig 7).…”

Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells

“…Finally, the type III PRMT, including PRMT7, catalyzes the mono- and symmetrically di-methylated arginine residues. Recently, we and others demonstrated the physiological roles for PRMT1, PRMT5 and PRMT8 in the control of neural function and neurodegenerative diseases 14–16 . Lin et al and Bowitch et al showed critical roles of PRMT8 and PRMT5 in the neural development of zebrafish 15 and of SER-2 tyramine receptor-mediated behaviors in Caenorhabditis elegans 16 , respectively.…”

“…Recently, we and others demonstrated the physiological roles for PRMT1, PRMT5 and PRMT8 in the control of neural function and neurodegenerative diseases 14–16 . Lin et al and Bowitch et al showed critical roles of PRMT8 and PRMT5 in the neural development of zebrafish 15 and of SER-2 tyramine receptor-mediated behaviors in Caenorhabditis elegans 16 , respectively. We have demonstrated that the PRMT1-mediated arginine methylation of the KCNQ channel contributes to the stabilization of neuronal excitability 14 .…”