Figure 2. Sources and clearance routes of pathologic cytoplasmic calcium response [Ca²⁺_i ].

Ryanodine Receptors (RyR) (34) and store operated calcium channels (SOCs) (35, 36) are major sources of Ca²⁺_i . RyRs are calcium sensitive channels, and open in response to mild rise in Ca²⁺_i although cADPR and NADDP are also possible RyR ligands (27-29, 33). The identity of SOCs and the mechanism of their regulation by ER calcium signals has been a field of active research. Recently TRPC3 and ORAI channels have been identified as important SOCs (35, 36) and it is postulated that STIMs that sit on ER membrane sense calcium depletion within the ER (as would occur after opening of RyRs) and migrate to plasma membrane where they open the SOCs (35, 36). Acidic pools are thought to be important in alcohol induced injury (30) and include organelles with low pH such as lysosomes, endososomes and zymogens. Recently recognized Two Pore Channels (TPCs) release calcium from acid pools (31-33). Mitochondria have been recognized as another source of calcium (not shown in the figure). Note that clearance of Ca²⁺_i is an ATP requiring process, and ATP depletion or direct inhibition of SERCA prolongs Ca²⁺_i , a mechanism thought to be important in pancreatic injury due to bile acids and ethanol metabolites.