Calcium release-activated channels (CRAC) are specialized plasma membrane Ca²⁺ ion channels. When calcium ions (Ca²⁺) are depleted from the endoplasmic reticulum (a major store of Ca²⁺) of mammalian cells, the CRAC channel is activated to slowly replenish the level of calcium in the endoplasmic reticulum. The Ca²⁺ Release-activated Ca²⁺ (CRAC) Channel (CRAC-C) Family (TC# 1.A.52) is a member of the Cation Diffusion Facilitator (CDF) Superfamily. These proteins typically have between 4 and 6 transmembrane α-helical spanners (TMSs). The 4 TMS CRAC channels arose by loss of 2TMSs from 6TMS CDF carriers, an example of 'reverse' evolution'.^[1]

Homology

There are several proteins that belong to the CRAC-C family. A list of the currently classified members of the CRAC-C family can be found in the Transporter Classification Database. This classification is based on sequence similarity which also happens to coincide with functional and structural similarities between homologues.

Structure

Almost all CRAC homologues are about 250 residues long, but some are up to 100 residues longer (e.g., the Drosophila melanogaster Olf186-F, TC# 1.A.52.1.5).

The plasma membrane protein "Orai" (ORAI1 and ORAI2 in humans) forms the pore of the CRAC channel. The protein ORAI1 is a structural component of the CRAC calcium channel. ORAI1 interacts with the STIM1 protein. STIM1 is a transmembrane protein of the endoplasmic reticulum (ER). STIM1 can sense the concentration of Ca²⁺ inside the ER. When the concentration of Ca²⁺ inside the ER becomes low, STIM1 proteins aggregate and interact with ORAI1 located in the cell surface membrane.^[2] When the concentration of Ca²⁺ inside the ER approaches an upper set point, another protein, SARAF (TMEM66) associates with STIM1 to inactivate the store-operated calcium channel (SOCE).^[3]

The crystal structure of Orai from Drosophila melanogaster has been determined at 3.35 angstrom resolution (PDB: 4HKR​).^[4] The calcium channel is composed of a hexameric assembly of Orai subunits arranged around a central ion pore. The pore traverses the membrane and extends into the cytosol. A ring of glutamate residues on its extracellular side forms the selectivity filter. A basic region near the intracellular side can bind anions that may stabilize the closed state. The architecture of the channel differs markedly from other ion channels and provides insight into the principles of selective calcium permeation and gating.^[4]

Function

In electrically non-excitable cells (i.e., blood cells), Ca²⁺ influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. Capacitative calcium entry appears to also be a major means of signal transduction. The major Ca²⁺ entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca²⁺ stores activates Ca²⁺ influx (store-operated Ca²⁺ entry, or capacitative Ca²⁺ entry). This is often referred to as the store-operated current or SOC.^[5]

A common mechanism by which such cytoplasmic calcium signals are generated involves receptors that are coupled to the activation of phospholipase C. Phospholipase C generates inositol 1,4,5-trisphosphate (IP3), which in turn mediates the discharge of Ca²⁺ from intracellular stores (components of the endoplasmic reticulum), allowing calcium to be released into the cytosol. In most of the cell, the fall in Ca²⁺ concentration within the lumen of the Ca²⁺-storing organelles subsequently activates plasma membrane Ca²⁺ channels.

See also

• Cation diffusion facilitator
• ORAI1
• ORAI2
• STIM1
• STIM2
• TRPC1
• Transporter Classification Database

References