MOLECULAR CHARACTERIZATION OF HUMAN AND RAT RGS-9L, A NOVEL SPLICE VARIANT ENRICHED IN DOPAMINE TARGET REGIONS, AND CHROMOSOMAL LOCALIZATION OF THE RGS-9 GENE

A novel splice variant of RGS 9 was isolated from a rat hypothalamus, human retina, and a human kidney (Wilm's) tumor. This variant, termed RGS 9L, differs from the retinal form (termed RGS 9S) identified previ ously in that it contains a 211-(rat) or 205- (human) amino acid proli ne-rich domain on the carboxyl terminus. The pattern of RGS 9 mRNA spl icing was tissue specific, with striatum, hypothalamus- and nucleus ac cumbens expressing RGS 9L, whereas retina and pineal expressed RGS 9S almost exclusively. This pattern of mRNA splicing seemed to be highly conserved between human and rodents, suggesting cell-specific differen ces in the function of these variants. Transient expression of RGS 9L augmented basal and beta-adrenergic receptor-stimulated adenylyl cycla se activity while suppressing dopamine D-2 receptor-mediated inhibitio n. Furthermore, RGS 9L expression greatly accelerated the decay of dop amine D-2 receptor-induced GIRK current. These results indicate RGS 9L inhibits heterotrimeric G(i) function in vivo, probably by acting as a GTPase-activating protein. The human RGS 9 gene was localized to chr omosome 17 q23-24 by radiation hybrid and fluorescent in situ hybridiz ation analyses. The RGS 9 gene is within a previously defined locus fo r retinitis pigmentosa (RP 17), a disease that has been linked to gene s in the rhodopsin/transducin/cGMP signaling pathway.