| The histidine-rich calcium-binding protein (HRCBP) is a calcium-binding protein expressed exclusively in the sarcoplasmic reticulum (SR) of muscle tissue in rabbit. Here we confirmed that HRCBP is also expressed specifically in striated muscle in the mouse and characterized its localization in the heart. We also examined the transcriptional regulation of HRC, the gene encoding HRCBP, during embryonic development by using the human HRC promoter to direct expression of a lacZ reporter construct in transgenic mice. This transgene was sufficient to direct expression specifically to the embryonic heart (8.5 dpc) and to the somites (9.0 dpc), the skeletal muscle precursors. Expression in the heart and skeletal muscle persisted throughout development and was also observed in arterial smooth muscle. Furthermore, expression in all three muscle lineages was dependent on a conserved MEF2 site, suggesting that MEF2 factors regulate the transcription of HRC and other SR genes.; HRCBP binds calcium in a high capacity low affinity manner reminiscent of other SR calcium buffering proteins. Furthermore, HRCBP localizes to the junctional SR and interacts with triadin, a component of the calcium release channel complex, suggesting that HRCBP is involved in calcium handling by the SR. To determine the function of HRCBP in vivo, we inactivated HRC, the gene encoding HRCBP, in mice. HRC knockout mice exhibited reduced body weight beginning at 11 months of age, which was marked by reduced skeletal muscle and fat mass. In addition, HRC null mice displayed a significantly exaggerated response to the induction of cardiac hypertrophy by isoproterenol compared to their wild type littermates.; Although we did not observe any significant defects in calcium handling in the hearts of HRC null mice, expression of the cardiac isoform of triadin (triadin 1) was upregulated in these hearts to compensate for the loss of HRCBP. These observations suggest that HRCBP may indirectly modulate inactivation of the ryanodine receptor (RyR) in response to changes in the luminal calcium concentration. Specifically, HRCBP may antagonize the inhibitory effect of calsequestrin on the ability of triadin to stabilize the open conformation of the RyR as luminal calcium stores are depleted. |
