Targeted therapy for neuropsychiatric disorders requires selective modulation of dysfunctional neuronal pathways. Genetic and biochemical studies have demonstrated that receptors relevant to CNS disorders typically have interacting proteins and auxiliary subunits that control their trafficking, gating and pharmacology. These receptor partners are often discretely expressed in specific neuronal pathways and provide a new dimension for drug discovery. Exemplary recent studies illustrate that the interface between AMPA receptor and a TARP auxiliary subunit provide a potent and druggable site. Small molecules binding this site modulate neuronal excitability in specific forebrain pathways relevant to subtypes of epilepsy as well as psychiatric and neurodegenerative disorders. Other medicinally-important ion channels, including kainate, NMDA, GABAA, nicotinic acetylcholine receptors and voltage dependent calcium and sodium channels, have essential associated proteins. This emerging pharmacology of receptor-associated proteins provides a new approach for improving drug efficacy while simultaneously mitigating side effects.
Host: Guoping Feng, McGovern Institute