Transgenic mouse hearts overexpressing the Ca(2+)-binding protein calsequestrin (CSQ) have an accompanying 10-fold increase in the sarcoplasmic reticulum (SR) Ca2+ load, however, exhibits slow and small Ca(2+)-induced Ca2+ release. Such slow kinetics of Ca2+ release may have activated excitation-transcription coupling as CSQ overexpressing hearts have induced levels of NFAT and GATA-4 activities and higher levels of c-fos mRNA and cFos protein compared to those of non-transgenic littermates. Adaptive responses, however, appear to downregulate transcriptional regulators controlling c-fos gene including serum response factor and Ca2+/cAMP response element-binding protein. CSQ-overexpressing hearts also had decreased levels of cJun protein, resulting in downregulated AP-1 activity. The mRNA levels of angiotensin II type1a receptor which requires AP-1 and GATA-4 for gene transcription was suppressed in CSQ overexpressing hearts. These results demonstrate that CSQ can regulate GATA-4- and AP-1-dependent transcriptional events, indicating the existence of SR-nuclear circuits of signal transduction in adult cardiac muscle.