Structural and biological approaches to further understand the physiology and pharmacology of the SK channels

Small conductance calcium-activated potassium (SK) channels are selective for K+ ions and are gated by Ca2+ via calmodulin molecules. These channels are expressed in various tissues and organs (e.g. nervous system, smooth muscle and heart) and play an important role in modulating the firing rate and firing pattern of different types of neurons. Three subtypes of SK subunits have been cloned and shown to be differentially expressed within the central nervous system. SK1 and SK2 are mostly expressed in the cortex and hippocampus while SK3 expression is higher in the monoamine cell regions. SK channels now represent potential targets for numerous central and peripheral nervous system disorders. Recently, new possibilities for treating diseases such as atrial fibrillation, schizophrenia or mood disorders were proposed. The development of new non-peptidic blockers combining high affinity and selectivity towards SK2 or SK3 channels is crucial and requires a better knowledge of the structural features essential to the affinity of these ligands.
In this project we study the 3D structures of SK proteins. From models obtained by using AlphaFold, we observed a particular conformation of the S3S4 loop in SK1, 2 and 3, which does not seem to be present in SK4. Furthermore, in the three first subtypes we observed the presence of a phenylalanine residue within this loop that appears to be located just at the exit of the pore of the channel and that could explain the lower currents displayed by those subtypes. Here we investigate this hypothesis by studying the activity and sensitivity to apamin of SK2 and SK3 channels mutated at this phenylalanine residue.