The “CaV2.2” channel, one of the voltage-gated calcium channels that control the influx of calcium ions and is expressed at the axon terminal of nerve cells to control neurotransmitter production, is crucial for signal transmission between nerve cells. Mental disorders such as bipolar disorder, schizophrenia, autism, epilepsy, and chronic pain have been associated with CaV2.2 activity regulation problems.

Phospholipids are the building blocks of the cell membrane. It is well known that the phospholipid PIP2 is crucial for the function of voltage-gated calcium channels. However, the exact mechanism by which PIP2 regulates calcium channel function has not been established due to the complex structure in which several subunits are bound.

The research team of Professor Suh Byung-chang from the Department of Brain Sciences, DGIST, identified the regulatory mechanism of calcium channels, which are essential for signal transmission between nerve cells. They studied the molecular mechanism of PIP2 related to the activation of various receptors and ion channels.

In particular, scientists have shown that the sensitivity of the voltage-gated calcium channel to PIP2 depends on the extent to which its auxiliary subunit, known as the 2 unit, is attached to the cell membrane.

These investigations served as the basis for this study, which aimed to determine the fundamental mechanism by which PIP2 regulates CaV2.2 activity differently depending on whether the 2 unit is physically or molecularly coupled to the cell membrane. The research team used genetic recombination to develop several mutant models of CaV2.2 channels and two units, which were then verified by electrophysiological methods.

As a result, it was found that PIP2 binds to the ‘I-II loop’ to which β2 units bind, in the CaV2.2 channel and to ‘S4II’, one of the voltage sensing domains, respectively, to regulate its activity. of the channel. In addition, it was found that the binding of PIP2 to the I-II loop is determined depending on whether the β2 unit binds to the cell membrane, thereby regulating the activity of CaV2.2.

Furthermore, it was confirmed that CaV2.2 activity can be regulated in real-time by developing a system that can artificially control the binding of PIP2 to the I-II loop of CaV2.2 by applying β2 moiety.

Scientists noted, “The result identified a novel mechanism of action for CaV2.2 channel activity, which plays a vital role in signal transmission between nerve cells. It is expected to be an important clue to the treatment of mental disorders, such as autism, bipolar disorder and schizophrenia, and of deadly neurological diseases, such as epilepsy and chronic pain in the future.”

Magazine reference:

  1. Cheon-Gyu Park, Wookyung Yu, Byung-Chang Suh, Molecular basis of the PIP2-dependent regulation of CaV2.2 channel and its modulation by CaV β subunits. eLife. DOI: 10.7554/eLife.69500