The carboxy-terminal hormone-binding domain of the TRα gene is alternatively-spliced to generate several protein products (Figure 3d-2, below). One variant, referred to as α-2, is identical to TRα-1 through the first 370 amino acids, but then its sequence diverges completely, owing to splicing of alternate exons (44-47). Another splicing variant, referred to as TRvII or α-3, is similar to α-2 except that it lacks the first 39 amino acids found in the unique region of α-2 (45). α -2 cannot bind TH because of the replacement of critical amino acids at the extreme carboxy-terminal end of the protein due to alternative splicing (48), and thus cannot mediate ligand-dependent gene transcription (49– 51). The amino acid replacements in α-2 also alter its dimerization properties and reduce DNA-binding affinity (52-55). The α-2 splicing variant is highly expressed in many tissues such as brain, testis, kidney, and brown fat, but its function remains poorly understood (56). The α-2 isoform has been proposed to be an endogenous inhibitor of TH receptor function as it inhibits TRα and β activity in transient gene expression assays (44,54). The mechanism by which α-2 antagonizes TR action is controversial. Some studies indicate that α-2 competes for active receptor complexes at DNA target sites (57,58). Other studies indicate that α-2 inhibits TR activity independent of DNA-binding (59). It is likely that the inhibitory effects of α-2 involve more than one mechanism. Amino acid substitutions in the carboxy-terminal region of α-2 also prevent its interactions with transcriptional corepressors (see below) (55), and may provide an explanation as to why α-2 is not a more potent inhibitor of TR activity. Additionally, the phosphorylation state of α-2 may modulate its inhibitory activity (60). Given the foregoing features, the TRα-1 and α-2 system represents one of the few examples in mammals whereby multiple mRNAs generated by alternative splicing encode proteins that are antagonistic to each other.