Hippocampal slice recordings revealed that GiGA1 activated natively expressed GIRK channels in hippocampal pyramidal neurons and decreased neuronal excitability (Table 1) [46]. In an acute epilepsy mouse model, the systemic application of GiGA1 (40 and 60 mg/kg) significantly reduced the severity and duration of seizures (Figure 3) [46]. Systemic GiGA1 exhibited good brain penetration. The fairly rapid metabolism (i.e., ≈30-min half-life) makes GiGA1 well-suited for acute treatments and perhaps limits the potential side-effects of GiGA1. At high doses, GiGA1 produced a sedative effect, which may need to be mitigated in future studies. Nonetheless, GiGA1 exhibits potential in controlling abnormal neuronal excitability and preventing overexcitation-induced neuronal damage. Moreover, the screening method in this study can be used in the future to identify subunit-specific GIRK modulators, such as targeting GIRK2 and GIRK3 subunits expressed in SNc and VTA dopamine neurons. A GIRK2 homotetramer or GIRK2/GIRK3 heterotetramer-specific activator is highly desirable as a potential anti-addictive drug, given their role in controlling dopamine release in drug addiction [55].
