Research ArticleGPCR SIGNALING

The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling

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Sci. Signal.  10 Nov 2015:
Vol. 8, Issue 402, pp. ra115
DOI: 10.1126/scisignal.aad0872

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Receptor methylation controls behavior

D2 dopamine receptors are targeted by antipsychotic agents to regulate behavior. Likhite et al. found putative arginine methylation motifs in some human G protein–coupled receptors (GPCRs), including the D2 dopamine receptor, and in homologs in the worm Caenorhabditis elegans. The protein arginine methyltransferase PRMT5 methylated D2 in vitro, and preventing this modification inhibited D2 receptor signaling in cultured cells. C. elegans lacking prmt-5 exhibited behavioral problems similar to those of worms deficient in the D2-like receptor DOP-3. This study not only shows that methylation modulates GPCR signaling but also suggests that this modification may be important for clinically relevant targets like the D2 receptor.

Abstract

Protein arginine methylation regulates diverse functions of eukaryotic cells, including gene expression, the DNA damage response, and circadian rhythms. We showed that arginine residues within the third intracellular loop of the human D2 dopamine receptor, which are conserved in the DOP-3 receptor in the nematode Caenorhabditis elegans, were methylated by protein arginine methyltransferase 5 (PRMT5). By mutating these arginine residues, we further showed that their methylation enhanced the D2 receptor–mediated inhibition of cyclic adenosine monophosphate (cAMP) signaling in cultured human embryonic kidney (HEK) 293T cells. Analysis of prmt-5–deficient worms indicated that methylation promoted the dopamine-mediated modulation of chemosensory and locomotory behaviors in C. elegans through the DOP-3 receptor. In addition to delineating a previously uncharacterized means of regulating GPCR (heterotrimeric guanine nucleotide–binding protein–coupled receptor) signaling, these findings may lead to the development of a new class of pharmacological therapies that modulate GPCR signaling by changing the methylation status of these key proteins.

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