Endoplasmic-reticulum calcium depletion and disease

The endoplasmic reticulum (ER) as an intracellular Ca2þ store not only sets up cytosolic Ca2þ signals, but, among other functions, also assembles and folds newly synthesized proteins. Alterations in ER homeostasis, including severe Ca2þ depletion, are an upstream event in the pathophysiology of many diseases. On the one hand, insufficient release of activator Ca2þ may no longer sustain essential cell functions. On the other hand, loss of luminal Ca2þ causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death. We will review these various diseases by mainly focusing on the mechanisms that cause ER Ca2þ depletion. Cytosolic [Ca 2þ] ([Ca2þ]cyt) is precisely regulated in time and space because Ca2þ controls essential cell functions like prolif-eration, differentiation, secretion, contraction, metabolism, trafficking, gene transcription and apoptosis, and in this way controls complex processes like development or learning behavior (Berridge et al. 2000). An abnormal [Ca2þ]cyt caused by disturbances of Ca2þ channels, Ca2þ transporters, Ca2þ pumps, and Ca2þ-binding proteins can induce multiple pathologies (Mis-siaen et al. 2000). Ca2þ channelopathies in the nervous system leading to paralysis, ataxia, or migraine can be caused by mutations in subunits of voltage-operated Ca2þ channels in the plasma membrane (Bidaud et al. 2006; Lorenzon and Beam 2008). Other channelopa-thies like malignant hyperthermia and central core disease in skeletal muscle, and some tachycardias and tachyarrhythmias in the heart are because of mutations in Ca2þ-release chan-nels or Ca2þ-binding proteins of the sarco-plasmic reticulum (SR) (Durham et al. 2007