  Due to alternative splicing in an ancestral DNA-binding domain (DBD) of the
mineralocorticoid receptor (MR), humans contain two almost identical MR
transcripts with either 984 amino acids (MR-984) or 988 amino acids (MR-988),
in which their DBDs differ by only four amino acids, Lys,Cys,Ser,Trp (KCSW).
Human MRs also contain mutations at two sites, codons 180 and 241, in the amino
terminal domain (NTD). Together, there are five distinct full-length human MR
genes in GenBank. Human MR-984, which was cloned in 1987, has been extensively
studied. Human MR-988, cloned in 1995, contains KCSW in its DBD. Neither this
human MR-988 nor the other human MR-988 genes have been studied for their
response to aldosterone and other corticosteroids. Here, we report that
transcriptional activation of human MR-988 by aldosterone is increased by about
50% compared to activation of human MR-984 in HEK293 cells transfected with the
TAT3 promoter, while the half-maximal response (EC50) is similar for
aldosterone activation of MR-984 and MR-988. Transcriptional activation of
human MR also depends on the amino acids at codons 180 and 241. Interestingly,
in HEK293 cells transfected with the MMTV promoter, transcriptional activation
by aldosterone of human MR-988 is similar to activation of human MR-984,
indicating that the promoter has a role in the regulation of the response of
human MR-988 to aldosterone. The physiological responses to aldosterone and
other corticosteroids in humans with MR genes containing KCSW and with
differences at codons 180 and 241 in the NTD warrant investigation.
