Novel Brain‐specific Isoforms of Regulator of G protein Signaling 6 (RGS6)

Katelin E Ahlers; Adele Stewart; Jianqi Yang; Zili Luo; Rory A Fisher

doi:10.1096/fasebj.30.1_supplement.865.2

Abstract only RGS proteins act as gatekeepers for cellular responses induced by G protein coupled receptors (GPCRs) by facilitating inactivation of heterotrimeric G protein signaling. By acting as GTPase activating proteins for Gα subunits, an activity bestowed by the semiconserved RGS domain present in all RGS members, RGS proteins determine the magnitude and duration of G protein signaling initiated by GPCRs. RGS6 is a member of the R7 subfamily distinguished by two additional unique domains, DEP/DHEX and GGL, which are important for membrane targeting and protein stability of these members, respectively. RGS6 specific modulation of Gα i/o protein activity has been implicated in regulation of several disease states, particularly in the CNS, including: alcoholism, anxiety/depression, and Parkinson's disease. In addition, RGS6 is unique in that it remains the only RGS7 family member that is known to regulate G protein‐independent pathways promoting pro‐apoptotic and growth suppressive actions in cancer. Potentially key to RGS6's G protein‐independent signaling as well as its modulation of G protein signaling are previously unidentified domains that arise via alternative mRNA splicing. Indeed, when our laboratory first cloned RGS6 from human brain we identified 36 distinct RGS6 isoforms. Recently, using western blot, we identified at least two additional RGS6 isoforms in the brain that are larger (~61 and 69kDa) than the ubiquitously expressed 56kDa form of the protein. The functions for these RGS6 variants and how they arise (either through protein modification or additional RNA splicing) is unknown. Here, we demonstrate that these brain specific isoforms, along with the 56kDa form, are robustly down‐regulated in human glioma, indicating they may be important for the prevention of tumorigenesis in the brain. In addition, utilizing RGS6 specific primers to perform PCR amplification of RGS6 from a human brain cDNA library (Clontech), we have discovered novel RGS6 species not identified in the initial cloning effort. These transcripts include novel exons, some of which appear to encode early stop codons and others which, when included in the final transcript, are predicted to produce proteins around the size of the brain specific isoforms previously identified by western blot. Interestingly, several of the identified exons appear to be shared primarily between humans and other primates. Together, this research will lay the groundwork for future experiments to elucidate the functional significance of RGS6 alternative mRNA splicing in normal brain function as well as pathology. Support or Funding Information NIH CA161882

Novel Brain‐specific Isoforms of Regulator of G protein Signaling 6 (RGS6)

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