Structure-function relations of calcium channels
It has been recognized for over two decades that depletion of the ER calcium store elicits calcium influx across the plasma membrane, a process known as "store-operated calcium entry (SOCE)". SOCE is best exemplified by the highly calcium-selective Ca release-activated Ca channels (CRAC) channels. CRAC channels contain a class of four-pass transmembrane proteins known as ORAI (named after the keepers of heaven's gate in Greek mythology) as their pore subunits, which are gated by ER-resident type I single-pass transmembrane proteins termed STIM. In addition, mitochondria play essential roles in maintaining CRAC channel activity by undergoing relocalization toward the plasma membrane, uptaking excessive calcium, diminishing calcium-dependent inactivation in activated cells, and thus prolonging the duration of SOCE. The residue E106 in the first transmembrane segment of ORAI1 plays a crucial role in calcium permeation and contributes to the high calcium selectivity of ORAI1 channels. Rare gene alleles that compromise CRAC channel expression or activation (e.g., R91W) result in severe immunodeficiency disease in human patients.
The discovery of SOCE mediated by ORAI and STIM also led to the recent acceleration of knowledge on the critical role of SOCE in cancer. Augmented SOCE has been found in a wide range of cancers and is significantly associated with the risk of tumor metastasis and survival. Therefore, the ORAI-STIM pathway could also serve as a novel target for anticancer therapeutic intervention.
Localization of GFP-STIM1 in Hela cells
Images acquired by Ji Jing.
- Following the identification of these two proteins, the major steps and certain regulatory mechanisms involved in the exquisite molecular choreography of SOCE have been under intense investigation. In particular, the structural basis, as well as the accompanying conformational changes underlying STIM-ORAI coupling between the ER and plasma membrane remains to be defined. Given that both CRAC channels and MCU have no discernible homology to other well-characterized channels, their ion permeation and gating mechanisms may represent totally new paradigms.
- The genetic basis of defective CRAC channel function in human SCID patients with inherited severe combined immunodeficiency has been traced back in loss-of-function mutations in either ORAI1 or STIM. Although both ORAI1 and STIM1 are widely expressed in different tissues, the major clinical consequences of defective CRAC channels are surprisingly limited to the immune system, skeletal muscle and ectodermally derived tissues. Similar phenotypes were recapitulated in mice with targeted disruptions of the Stim1, Stim2 and Orai1 genes. Thus, small molecule inhibitors that specifically target the STIM-ORAI pathway have a high potential to suppress immune function selectively and may lack the toxicity of current immunosuppressive agents, such as cyclosporine A and FK506.When targeted to tumor cells in the form of antibody-drug conjugates, SOC inhibitors may find their broad use in attenuating tumor growth, migration and metastasis.
adapted from ARI 2010
Initial activation of STIM1