Because XLαs shares significant amino acid identity with Gsα, it comprises most domains of the latter shown to be functionally important. Furthermore, the C-terminal end of the XL domain has significant homology to the exon 1 encoded portion of Gsα. Consistent with the high degree of overall similarity between XLαs and Gsα, various studies have demonstrated that XLαs is able to act in a manner similar to Gsα in vitro. First, XLαs show enhanced ADP ribosylation and an increased sucrose-density sedimentation rate upon addition of the Gβγ subunits, indicating that XLαs is able to form a heterotrimer [69]. Second, expression of an XLαs mutant carrying the homolog of the Gsα Gln227 mutation results in elevated cAMP formation, indicating that XLαs can stimulate adenylyl cyclase at least in the basal state [69]. Third, XLαs can mediate receptor-stimulated cAMP formation when overexpressed in opossum kidney cells that show endogenous Gsα expression [70] and in mouse embryonic fibroblasts that endogenously lack Gsα and XLαs due to homozygous disruption of Gnas exon 2 [71]. Finally, mutations that impair Gsα activity have similar effects on
