Science CommuniCa2+tion Developing Scientific Literacy on Calcium: The Involvement of CRAC Currents in Human Health and Disease

Abstract

All human life starts with a calcium (Ca²⁺) wave. This ion regulates a plethora of cellular functions ranging from fertilisation and birth to development and cell death. A sophisticated system is responsible for maintaining the essential, tight concentration of calcium within cells. Intricate components of this Ca²⁺ network are store-operated calcium channels in the cells' membrane. The best-characterised store-operated channel is the Ca²⁺ release-activated Ca²⁺ (CRAC) channel. Currents through CRAC channels are critically dependent on the correct function of two proteins: STIM1 and Orai1. A disruption of the precise mechanism of Ca²⁺ entry through CRAC channels can lead to defects and in turn to severe impacts on our health. Mutations in either STIM1 or Orai1 proteins can have consequences on our immune cells, the cardiac and nervous system, the hormonal balance, muscle function, and many more. There is solid evidence that altered Ca²⁺ signalling through CRAC channels is involved in the hallmarks of cancer development: uncontrolled cell growth, resistance to cell death, migration, invasion, and metastasis. In this work we highlight the importance of Ca²⁺ and its role in human health and disease with focus on CRAC channels.

Keywords: Orai; STIM; calcium; cancer; disease; science communication; science literacy; store-operated channels; therapeutic target.

Figure 1

Calcium function from whole organism to single cell level. (Left): Biological processes and systems that depend on calcium. Yellow circles schematically mark sites affected by calcium-related diseases within the human body such as the brain, lungs, heart, muscles, and the immune system. (Right—middle lane): Scheme of a human cell. At resting conditions, calcium (purple) is stored within the ER. At this stage, calcium is bound to STIM1 proteins (green) which are in an inactive state. As soon as calcium stores are emptied, STIM1 loses the bound calcium, elongates, and communicates with Orai1 in the plasma membrane (red). Subsequently, calcium ions enter the cell from the extracellular milieu, trigger calcium-dependent responses, and the ER calcium stores are refilled as well. (Right—upper and lower lane): Live-cell fluorescent images of human embryonic kidney (HEK293) cells to visualise the localisation of STIM1 (green) and Orai1 (red) proteins within the cell. With full ER-calcium stores, both proteins are evenly distributed (upper lane). Upon emptying of the ER store, both proteins locate at sites called puncta where they interact (lower lane). (Image created by A.B.).