Paclitaxel (Taxol) is a well established chemotherapeutic agent for the treatment of solid tumors, but it is limited in its usefulness by the frequent induction of peripheral neuropathy. We found that prolonged exposure of a neuroblastoma cell line and primary rat dorsal root ganglia with therapeutic concentrations of Taxol leads to a reduction in inositol trisphosphate (Ins P ₃ )-mediated Ca ²⁺ signaling. We also observed a Taxol-specific reduction in neuronal calcium sensor 1 (NCS-1) protein levels, a known modulator of Ins P ₃ receptor (Ins P ₃ R) activity. This reduction was also found in peripheral neuronal tissue from Taxol treated animals. We further observed that short hairpin RNA-mediated NCS-1 knockdown had a similar effect on phosphoinositide-mediated Ca ²⁺ signaling. When NCS-1 protein levels recovered, so did Ins P ₃ -mediated Ca ²⁺ signaling. Inhibition of the Ca ²⁺ -activated protease μ-calpain prevented alterations in phosphoinositide-mediated Ca ²⁺ signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by μ-calpain in vitro and that μ-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates μ-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates Ins P ₃ mediated Ca ²⁺ signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.

Altered regulation of signaling pathways can lead to pathologies including cardiac hypertrophy and heart failure. We report that neonatal and adult cardiomyocytes express chromogranin B (CGB), a Ca ²⁺ binding protein that modulates Ca ²⁺ release by the inositol 1,4,5-trisphosphate receptor (InsP ₃ R). Using fluorescent Ca ²⁺ indicator dyes, we found that CGB regulates InsP ₃ -dependent Ca ²⁺ release in response to angiotensin II, an octapeptide hormone that promotes cardiac hypertrophy. ELISA experiments and luciferase reporter assays identified angiotensin II as a potent inducer of brain natriuretic peptide (BNP), a hormone that recently emerged as an important biomarker in cardiovascular disease. CGB was found to regulate angiotensin II–stimulated and basal secretion, expression and promoter activity of BNP that depend on the InsP ₃ R. Moreover, we provide evidence that CGB acts via the transcription activity of nuclear factor κB in an InsP ₃ /Ca ²⁺ -dependent manner but independent of nuclear factor of activated T cells. In vivo experiments further showed that cardiac hypertrophy induced by angiotensin II, a condition characterized by increased ventricular BNP production, is associated with upregulation of ventricular CGB expression. Overexpression of CGB in cardiomyocytes, in turn, induced the BNP promoter. The evidence presented in this study identifies CGB as a novel regulator of cardiomyocyte InsP ₃ /Ca ²⁺ -dependent signaling, nuclear factor κB activity, and BNP production.

The clinical effect of copper accumulation on the heart of patients suffering from Wilson’s disease (WD) is not completely understood. We aimed to determine if patients with WD show signs of cardiac involvement, structural heart disease or autonomic dysfunction. In this prospective trial, we studied 61 patients (mean age 44.3 ± 15.2 years, 51% males) with WD and compared them to 61 age- and gender-matched healthy controls. All subjects underwent clinical examination, blood tests, echocardiography and 24 h electrocardiographic (ECG) recording. Left- and right ventricular systolic function did not differ significantly between WD patients and controls. However, 5 of the 61 patients had a reduced left ventricular ejection fraction (LVEF). Furthermore, diastolic dysfunction was more prevalent in WD patients (9 of 61 vs. 0 of 61, p = 0.001). The severity of WD based on the Unified Wilson’s Disease Rating Scale was significantly correlated to NT-pro BNP (r = 0.34, P = 0.013). Patients with an exacerbation of WD in medical history had higher troponin levels compared to those without (11.3 ± 4.7 vs 4.6 ± 1.2). The autonomic function assessed by triangular index (TI) and SDNN-index was significantly reduced in WD patients compared to controls in most in almost every age category (p-value TI and SDNN: age 20–29, p < 0.001 and 0.05; age 30–39, p < 0.01 and not significant (ns); age 40–49, p < 0,01 and 0.001; age 50–59, p = ns and < 0.001, age 60–70, p < 0.05 and ns). Our data demonstrate that cardiac involvement and autonomic dysfunction in WD is possible, however the underlying cause is still not known. We suggest that patients with signs and symptoms of structural heart disease should be examined by a cardiologist in addition to the interdisciplinary treatment team of WD.