CRAC channels and disease - From human CRAC channelopathies and animal models to novel drugs

Abstract

Ca²⁺ release-activated Ca²⁺ (CRAC) channels are intimately linked with health and disease. The gene encoding the CRAC channel, ORAI1, was discovered in part by genetic analysis of patients with abolished CRAC channel function. And patients with autosomal recessive loss-of-function (LOF) mutations in ORAI1 and its activator stromal interaction molecule 1 (STIM1) that abolish CRAC channel function and store-operated Ca²⁺ entry (SOCE) define essential functions of CRAC channels in health and disease. Conversely, gain-of-function (GOF) mutations in ORAI1 and STIM1 are associated with tubular aggregate myopathy (TAM) and Stormorken syndrome due to constitutive CRAC channel activation. In addition, genetically engineered animal models of ORAI and STIM function have provided important insights into the physiological and pathophysiological roles of CRAC channels in cell types and organs beyond those affected in human patients. The picture emerging from this body of work shows CRAC channels as important regulators of cell function in many tissues, and as potential drug targets for the treatment of autoimmune and inflammatory disorders.

Keywords: CRAC channel; Calcium; Disease; Immunodeficiency; Mutation; ORAI1; STIM1.

Figure 1.. CRAC channelopathy in human patients.

Loss-of-function (LOF) mutations in ORAI1 and STIM1 genes result in combined immunodeficiency with chronic, often lethal infections and a variety of non-immunological symptoms. For details see [14, 30]. AIHA, autoimmune hemolytic anemia.

Figure 2.. Clinical phenotype of patients with Stormorken syndrome and tubular aggregate myopathy.

Gain-of-function (GOF) mutations in ORAI1 and STIM1. For details see [15]. CK, creatinine kinase.

Figure 3.. Animal models of CRAC channel function in health and disease in mice.

Organs in which CRAC channels play a role in physiological function or disease pathology as examined by reviews in this special issue of Cell Calcium [–25].

Cover picture:

Dionysos leading the Horai. Marble, Roman copy (1st century CE) after a Hellenistic neo-Attic work. Artist unknown. Musée du Louvre. NOTE: This is a public domain image. Details at: https://commons.wikimedia.org/wiki/File:Dionysos_Horai_Louvre_MR720.jpg