Opening closed inward rectifier potassium channel doors

Inwardly rectifying potassium (K_IR) channels are essential regulators of membrane potential in excitable and non-excitable tissues. Although K_IR channels exhibit a biophysical preference for potassium influx due to voltage-dependent block of outward current by polyamines and Mg²⁺, under physiological conditions, they predominantly mediate K⁺ efflux. This outward current not only is essential for stabilizing the resting membrane potential, limiting cellular excitability and coordinating rhythmic activity in excitable tissues such as the heart and muscle, but also functions in endocrine and exocrine organs and neural tissues. A growing list of pathogenic K_IR mutations that reduce or abolish channel activity has been linked to channelopathies, including Andersen syndrome and EAST/SeSAME syndrome, among others. These loss-of-function phenotypes underscore the therapeutic need for selective K_IR channel activators. However, pharmacological tools remain limited and subtype-selective activation is rare. Small molecules such as ML297 selectively activate K_ir3.1/3.2-containing channels, whereas GiGA1 and VU0529331 target K_ir3.2-containing subunits. Several clinically used drugs (e.g. propafenone) modulate K_ir2.1 and novel compounds such as GPV0057 show improved selectivity. However, no K_IR channel activators have advanced to clinical trials and key subtypes such as K_ir1.1 and K_ir7.1 lack known openers. This review evaluates the current knowledge of K_IR-targeted agonists, with a focus on their potential to address PIP₂-dependent loss-of-function mutations in K_IR channels. We emphasize the urgent need for subtype-specific K_IR openers, the development of PIP₂-independent mechanisms of action and comprehensive preclinical characterization to overcome translational barriers. Addressing these challenges may provide new therapeutic opportunities for rare channelopathies associated with K_IR channel dysfunction.