Figure 1. CRACkdown on pancreatitis. Gerasimenko et al. have found that blocking calcium release-activated calcium channels (CRACs) could prevent the calcium (Ca2+)-mediated cytotoxicity that leads to acute pancreatitis.

CRACs consist of channel subunits such as transmembrane protein 142A (ORAI1; TMEM142A; CRACM1) and calcium-sensing sub-units such as stromal interaction molecule 1 (STIM1).

Gerasimenko et al. propose that in pancreatic acinar cells, high levels of alcohol lead to formation of fatty acid ethyl esters [a] that cause depletion of calcium stores in the endoplasmic reticulum [b] and activate STIM1 [c]. STIM1 binds to and activates CRACM1 [d], which then opens to allow extracellular calcium to flow into the cytoplasm [e], leading to cytotoxicity, necrosis and pancreatitis [f].

GSK-7975A, a CRACM1 antagonist developed as a research reagent at GlaxoSmithKline plc for respiratory indications, prevented acinar cell toxicity caused by fatty acid ethyl esters.

CalciMedica Inc. and Synta Pharmaceuticals Corp. have CRACM1 antagonists in preclinical development for autoimmune and inflammatory indications.