A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action

Aldosterone effects are mediated by the MR, which possesses the same affini ty for mineralocorticoids and glucocorticoids. In addition to the existence of mechanisms regulating intracellular hormone availability, we searched f or human MR splice variants involved in tissue-specific corticosteroid func tion. We have identified a new human MR isoform, hMR Delta5,6, resulting fr om an alternative splicing event skipping exons 5 and 6 of the human MR gen e. hMR Delta5,6 mRNAs are expressed in several human tissues at different l evels compared with wild-type human MR, as shown by real time PCR. Introduc tion of a premature stop codon results in a 75-kDa protein lacking the enti re hinge region and ligand binding domain. Interestingly, hMR Delta5,6 is s till capable of binding to DNA and acts as a ligand-independent transactiva tor, with maximal transcriptional induction corresponding to approximately 30-40% of aldosterone-activated wild-type human MR. Coexpression of hMR Del ta5,6 with human MR or human GR increases their transactivation potential a t high doses of hormone. Finally, hMR Delta5,6 is able to recruit the coact ivators, steroid receptor coactivator 1, receptor interacting protein 140, and transcription intermediary factor 1 a, which enhance its transcriptiona l activity. Ligand-independent transactivation and enhancement of both wild -type MR and GR activities by hMR Delta5,6 suggests that this new variant m ight play a role in modulating corticosteroid effects in target tissues.