TRPC channels (Transient Receptor Potential Canonical) represent a fundamental group of membrane proteins that allow the passage of calcium and other cations through the cell membrane in many types of human and animal cells. They are essential for the proper functioning of the nervous system, kidneys, muscles, and sensory neurons, and they play roles in regulating pain, metabolism, blood pressure, as well as in acute and chronic inflammatory processes. The latest research from the Laboratory of Cellular Neurophysiology of the IPHYS provides a detailed description of the molecular mechanism by which the R175C mutation in the TRPC5 channel disrupts its function and contributes to the development of intellectual disability and autism. The authors used a combination of computer simulations, targeted mutagenesis, and electrophysiology to uncover a key regulatory region at the cytoplasmic interface of the channel subunits. They showed that the distribution of hydrogen bonds in this region regulates the transition between the open and closed states of the channel. Furthermore, they identified serine 193 as a site of post-translational modification with a significant impact on channel activity. These findings published in the journal Neurobiology of Disease substantially expand knowledge of the intracellular regulation of TRPC channels and open new avenues for targeted treatment of neurological diseases associated with their dysfunction.
Reference: Mitro M., Ptáková A., Vlachová V., Zímová L.: Cytoplasmic inter-subunit interface modulates TRPC5 activity: Molecular mechanism behind intellectual disability-related R175C mutation. Neurobiology of Disease 215:107082 (2025). IF = 5.6; DOI: 10.1016/j.nbd.2025.107082
