Thyroid hormone (T3) increases the transcription of the sarcoplasmic reticulum 
Ca2+ adenosine triphosphatase (ATPase) gene (SERCA 2) through three thyroid 
hormone response elements. The existence of repetitive cis elements with 
different configurations is likely to serve specific functions such as 
interactions with nuclear transcription factors. In addition, the presence of 
different T3 receptor isoforms (T3Rs) may contribute to another level of 
complexity in providing specificity for T3 action. In this study, we 
investigated T3R alpha 1-vs. T3R beta 1-specific interactions with the myocyte 
enhancer-specific factor-2 (MEF-2) on the expression of the SERCA 2 gene in 
transient transfection assays in embryonal heart-derived H9c2 cells. MEF-2a in 
combination with either T3R alpha 1 or T3R beta 1 isoforms resulted in a 
2.5-fold increase in SERCA 2 transgene expression in the absence of T3. Addition 
of T3 did not induce any further increase in SERCA 2 expression when T3R alpha 1 
and MEF-2a expression vectors were cotransfected. In contrast, in the presence 
of T3R beta 1 and MEF-2, the addition of T3 increased chlorampenicol 
acetyltransferase activity by an additional 2.2-fold to a total 5.5-fold 
increase. The interaction between MEF-2a and T3R is transcription factor 
specific because another factor that binds to MEF-2 consensus sites (heart 
factor 1b) was not able to interact with T3R. In addition, MEF-2a failed to 
interact with other nuclear factors (cAMP response element-binding protein and 
Egr-1) that stimulate SERCA 2 gene transcription. In addition, we found that a 
single homologous thyroid hormone response element is not able to mediate the 
interactions between MEF-2a and T3Rs to increase SERCA 2 gene transcription. Our 
findings point to T3R isoform-specific interactions with a cell type-specific 
transcription factor (MEF-2) in the regulation of SERCA 2 gene expression.