A large body of literature describes the mechanisms of excitation- contraction coupling and relaxation in mature cardiac muscle. Although developing hearts exhibit profound differences in contraction and relaxation processes compared with adults, considerably less information is available regarding calcium regulation in the immature heart. Based on our earlier work and other laboratory reports, we focus on characterizing the sarcolemmal Na+-Ca2+ exchanger in the developing heart. Our initial studies demonstrated that exchanger protein content was highest at birth and correlated with greater Na+-dependent Ca2+ uptake in fetal and newborn sarcolemmal vesicles. Subsequently, we found that late fetal and early newborn hearts contain approximately sixfold higher steady-state mRNA levels for the exchanger, compared with adult myocardium. Furthermore, changes in exchanger protein content and mRNA levels correlated with the age-related changes in Na+-Ca2+ exchange current density recorded in isolated myocytes. Most recently, we demonstrated that thyroid hormone, which surges at birth and affects expression of several important cardiac genes, regulates exchanger expression in immature and adult myocardium. We have planned various experiments to be performed in the developing heart to determine: 1) the contribution of Ca2+ influx via the exchanger ("reverse" exchange) to contraction, 2) the physiological role of the exchanger in relaxation, 3) molecular mechanisms involved in the neurohumoral and developmental regulation of exchanger expression, and 4) the consequences of perturbing the normal expression of Na+-Ca2+ exchange. These studies will have important implications for understanding fundamental mechanisms of normal and abnormal cardiac contractile function in immature and adult hearts.