RGS proteins are defined by the presence of a semiconserved RGS domain that 
confers the GTPase-activating activity of these proteins toward certain G alpha 
subunits. RGS6 is a member of a subfamily of RGS proteins distinguished by the 
presence of DEP and GGL domains, the latter a G beta 5-interacting domain. Here 
we report identification of 36 distinct transcripts of human RGS6 that arise by 
unusually complex processing of the RGS6 gene, which spans 630 kilobase pairs of 
genomic DNA in human chromosome 14 and is interrupted by 19 introns. These 
transcripts arise by use of two alternative transcription sites and complex 
alternative splicing mechanisms and encode proteins with long or short 
N-terminal domains, complete or incomplete GGL domains, 7 distinct C-terminal 
domains and a common internal domain where the RGS domain is found. The role of 
structural diversity in the N-terminal and GGL domains of RGS6 splice variants 
in their interaction with G beta 5 and subcellular localization and of G beta 5 
on RGS6 protein localization was examined in COS-7 cells expressing various RGS6 
splice variant proteins. RGS6 splice variants with complete GGL domains 
interacted with G beta 5, irrespective of the type of N-terminal domain, while 
those lacking a complete GGL domain did not. RGS6 protein variants displayed 
subcellular distribution patterns ranging from an exclusive cytoplasmic to 
exclusive nuclear/nucleolar localization, and co-expression of G beta 5 promoted 
nuclear localization of RGS6 proteins. Analysis of our results show that the 
long N-terminal and GGL domain sequences of RGS6 proteins function as 
cytoplasmic retention sequences to prevent their nuclear/nucleolar accumulation. 
These findings provide the first evidence for G beta 5-independent functions of 
the GGL domain and for a role of G beta 5 in RGS protein localization. This 
study reveals extraordinary complexity in processing of the human RGS6 gene and 
provides new insights into how structural diversity in the RGS6 protein family 
is involved in their localization and likely function(s) in cells.