A role for calreticulin in the adult heart?

essential role of calcium in cardiac development, function, and disease is incontrovertible. The multiple pathways that regulate Ca 2+ home-ostasis in the heart are complex and frequently intersecting, involving a large number of myocyte proteins. One protein that is emerging as having a central role in Ca 2+ homeostasis and in cardiac development is the ubiquitous chaperone protein of the endoplasmic reticulum (ER), calretic-ulin. Over 40 different functions have been ascribed to this Ca 2+-binding protein, including regulation of gene expression, protein folding, cell adhesion , and autoimmunity (reviewed in ref. 1). In the mouse heart, calretic-ulin expression is activated at 9.5 days postcoitum (dpc) and remains high until 14.5 dpc. Expression is relatively low by 18 dpc and is barely detectable postnatally. Mice in which the Calreticulin gene has been inacti-vated die by 14.5 dpc, primarily due to cardiac defects with a marked decrease in ventricular wall thickness (2). Therefore, the importance of cal-reticulin in cardiac development has been solidified, although its specific role remains unclear. In this issue of JCI, Nakamura and colleagues (3) have forced expression of calreticulin in adult cardiac myocytes in the mouse, to study the sequelae of sustained high expression of this protein after development. These animals exhibit decreased systolic function, chamber dilation, and wall thinning, and they die of sudden cardiac death (3). This premature death is associated with complete heart block. While the mechanisms behind these phenotypes remain somewhat unclear, there is a significant decrease in inward Ca 2+ current as well as a decrease in expression of connexins 40 and 43. Consistent with a role for the connexins in the phenotypes of the mice is the finding that inactiva-tion of connexin43 in adult cardiac myocytes results in severe arrhyth-mias (4). In addition, mice lacking connexin40 exhibit sinoatrial, intra-atrial, and atrioventricular conduction disturbances (5). The complete heart block in calreticulin-overex-pressing mice might therefore be explained, at least in part, by secondary changes in expression of other proteins, including the connexins. Since other proteins that have been implicated in cardiac pathogenesis, including SERCA2, phospholamban, calsequestrin, and β-myosin heavy chain, remain unchanged in this model, the decrease in connexins 40 and 43 appears to be a relatively specific consequence of expressing the transgene. Still, reduced connexin levels seem unlikely to explain all of its effects, since the conditional and complete null mice for connexins 40 and 43, respectively, do not exhibit dilation and systolic …