Nuclear calcium (Ca 2؉ ) regulates a number of important cellular processes, including gene transcription, growth, and apoptosis. However, it is unclear whether Ca 2؉ signaling is regulated differently in the nucleus and cytosol. To investigate this possibility, we examined subcellular mechanisms of Ca 2؉ release in the HepG2 liver cell line. The type II isoform of the inositol 1,4,5-trisphosphate (InsP 3) receptor (InsP 3R) was expressed to a similar extent in the endoplasmic reticulum and nucleus, whereas the type III InsP 3R was concentrated in the endoplasmic reticulum, and the type I isoform was not expressed. Ca 2؉ signals induced by low InsP3 concentrations started earlier or were larger in the nucleus than in the cytosol, indicating higher sensitivity of nuclear Ca 2؉ stores for InsP3. Nuclear InsP3R channels were active at lower InsP 3 concentrations than InsP3R from cytosol. Enriched expression of type II InsP 3R in the nucleus results in greater sensitivity of the nucleus to InsP 3, thus providing a mechanism for independent regulation of Ca 2؉ -dependent processes in this cellular compartment.

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We report here the ®rst three-dimensional structure of the type 1 inositol 1,4,5-trisphosphate receptor (IP 3 R). From cryo-electron microscopic images of puri®ed receptors embedded in vitreous ice, a threedimensional structure was determined by use of standard single particle reconstruction techniques. The structure is strikingly different from that of the ryanodine receptor at similar resolution despite molecular similarities between these two calcium release channels. The 24 A Ê resolution structure of the IP 3 R takes the shape of an uneven dumbbell, and is 170 A Ê tall. Its larger end is bulky, with four arms protruding laterally by~50 A Ê and, in comparison with the receptor topology, probably corresponds to the cytoplasmic domain of the receptor. The lateral dimension at the height of the protruding arms is 155 A Ê . The smaller end, whose lateral dimension is 100 A Ê , has structural features indicative of the membrane-spanning domain. A central opening in this domain, which is occluded on the cytoplasmic half, outlines a pathway for calcium¯ow in the open state of the channel.

Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer.Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer.Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.