Lily Kisseur

Channelopathies such as cystic fibrosis and epilepsy are diseases caused by mutations in ion channels. Ion channels, which are located in cell membranes, facilitate fundamental biological processes such as pacemaking, muscle contraction, and sensory transduction by controlling the influx of charged ions intra and extracellular. Voltage-gated ion channels open in response to depolarization, which is when the negatively charged intracellular environment becomes too positive due to the influx of positively charged ions coming into the cell. The voltage sensor domain (VSD) is responsible for opening voltage-gated ion channels in response to depolarization. On the other hand, ligand-gated ion channels open when a ligand like cAMP or cGMP binds to its receptor. In this research paper, the VSD of SthK, a cyclic nucleotide-gated ion channel (CNG) derived from the Spirochaeta thermophila bacteria is modulated to let cAMP effectively activate the channel.CNG channels are voltage-gated channels responsible for the function of visual and olfactory senses. Although SthK is a voltage-gated ion channel, it works more like a ligand-gated ion channel because it opens in response to cGMP or cAMP binding to its receptor. While cGMP is able to open the Sthk channel within milliseconds, cAMP is not as effective. Through modulating the VSD, cAMP is able to open the channel, though not as quickly as cGMP, suggesting that the VSD is responsible for the effectiveness of a ligand's ability to activate a channel. When cAMP was modified, it allowed researchers to easily observe intermediate structures between the open and closed states of an ion channel. By investigating these otherwise unstable states researchers are better able to understand how the VSD mutations are able to make cAMP capable of fully opening CNG ion channels. Understanding the relationship between VSDs and ligand gating is crucial to the creation of future therapeutics that treat channelopathies.