Park, Eonyoung and Iaccarino, Ciro and Lee, Jiwon and Kwon, Ilmin and Baik, Sun Mi and Kim, Myungjin and Seong, Jae Young and Son, Gi Hoon and Borrelli, Emiliana and Kim, Kyungjin (2011) Regulatory roles of heterogeneous nuclear ribonucleoprotein M and nova-1 protein in alternative splicing of dopamine D2 receptor pre-mRNA. The Journal of Biological Chemistry, Vol. 286 (28), p. 25301-25308. eISSN 1083-351X. Article.
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The dopamine D2 receptor (D2R) plays a crucial role in the regulation of diverse key physiological functions, including motor control, reward, learning, and memory. This receptor is present in vivo in two isoforms, D2L and D2S, generated from the same gene by alternative pre-mRNA splicing. Each isoform has a specific role in vivo, underlining the importance of a strict control of its synthesis, yet the molecular mechanism modulating alternativeD2Rpre-mRNA splicing has not been completely elucidated. Here, we identify heterogeneous nuclear ribonucleoproteinM(hnRNP M) as a key molecule controlling D2R splicing. We show that binding of hnRNP M to exon 6 inhibited the inclusion of this exon in the mRNA. Importantly, the splicing factor Nova-1 counteracted hnRNP M effects on D2R premRNAsplicing. Indeed, mutations of the putative Nova-1-binding site on exon 6 disrupted Nova-1 RNA assembly and diminished the inhibitory effect of Nova-1 on hnRNP M-dependent exon 6 exclusion. These results identify Nova-1 andhnRNPMas D2R pre-mRNA-binding proteins and show their antagonistic role in the alternative splicing of D2R pre-mRNA.
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