Molecular dynamics simulations reveal the hidden EF-hand of EF-SAM as a possible key thermal sensor for STIM1 activation by temperature.

Intracellular calcium signaling is essential for many cellular processes, including store-operated Ca entry (SOCE), which is initiated by stromal interaction molecule 1 (STIM1) detecting endoplasmic reticulum (ER) Ca depletion. STIM1 is also activated by temperature independent of ER Ca depletion. Here we provide evidence, from advanced molecular dynamics simulations, that EF-SAM may act as a true temperature sensor for STIM1, with the prompt and extended unfolding of the hidden EF-hand subdomain (hEF) even at slightly elevated temperatures, exposing a highly conserved hydrophobic Phe108.

Orai1- and Orai2-, but not Orai3-mediated I is regulated by intracellular pH.

Three Orai (Orai1, Orai2, and Orai3) and two stromal interaction molecule (STIM1 and STIM2) mammalian protein homologues constitute major components of the store-operated Ca entry mechanism. When co-expressed with STIM1, Orai1, Orai2 and Orai3 form highly selective Ca channels with properties of Ca release-activated Ca (CRAC) channels. Despite the high level of homology between Orai proteins, CRAC channels formed by different Orai isoforms have distinctive properties, particularly with regards to Ca -dependent inactivation, inhibition/potentiation by 2-aminoethyl diphenylborinate and sensitivity to reactive oxygen species.

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species.

TRPM2 channels admit Ca and Na across the plasma membrane and release Ca and Zn from lysosomes. Channel activation is initiated by reactive oxygen species (ROS), leading to a subsequent increase in ADP-ribose and the binding of ADP-ribose to an allosteric site in the cytosolic NUDT9 homology domain. In many animal cell types, Ca entry via TRPM2 channels mediates ROS-initiated cell injury and death.

Targeting Ca Signaling in the Initiation, Promotion and Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a considerable health burden worldwide and a major contributor to cancer-related deaths. HCC is often not noticed until at an advanced stage where treatment options are limited and current systemic drugs can usually only prolong survival for a short time. Understanding the biology and pathology of HCC is a challenge, due to the cellular and anatomic complexities of the liver.

Deranged hepatocyte intracellular Ca homeostasis and the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in men, and the sixth in women. Non-alcoholic fatty liver disease (NAFLD) is now one of the major risk factors for HCC. NAFLD, which involves the accumulation of excess lipid in cytoplasmic lipid droplets in hepatocytes, can progress to non-alcoholic steatosis, fibrosis, and HCC.