Chemogenetic Ion Channels (PSAM / PSEM)

PSAMs — Pharmacologically Selective Actuator Modules — are engineered ligand-gated ion channels rather than G-protein-coupled receptors: a mutated ligand-binding domain (derived from a nicotinic receptor) is fused to an ion-conducting pore, and the channel opens only when bound by an ultrapotent synthetic ligand, the matching PSEM (Pharmacologically Selective Effector Molecule). Because the conductance is chosen by the pore, the same platform can be made cation-selective for excitation or chloride-selective for inhibition.

Being ionotropic, PSAM/PSEM systems act directly on membrane current with faster onset and offset than metabotropic DREADDs, and offer a cleaner separation of the actuator from native signalling. Newer versions have been engineered so that their ligand is a clinically-approved drug at ultralow, subpharmacological doses, which is one of the more concrete paths toward a chemogenetic therapy in humans.