ArticleNature communications2026
PIP2 binding at allosteric site blocks activation in human rod CNG channels.
Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Phosphatidylinositol-4,5-bisphosphate (PIP2) is a signaling lipid that regulates multiple ion channels. In rod cyclic nucleotide-gated (CNG) channels, PIP2 was reported to inhibit activity, controlling light sensitivity and dynamic range. Reports of low PIP2 levels in rod outer segment (ROS) membranes questioned the physiological relevance of such inhibition, and the underlying mechanism remained unclear. Here we define the mechanism of PIP2 inhibition of human CNGA1, the principal rod CNG channel subunit. Flux assays and single-channel electrophysiology of purified, liposome-reconstituted CNGA1 channels demonstrate inhibition at PIP2 concentrations estimated for ROS membranes. Cryo-EM structures of PIP2-free channels in lipid nanodiscs capture closed, intermediate, and open conformations, whereas the open state is absent with PIP2. PIP2 binds at the interface between voltage-sensing, pore, and C-linker domains, stabilizing closed states and sterically preventing channel opening. Our findings establish the physiological relevance and structural mechanism of PIP2 inhibition, and provide an inhibitory allosteric site for therapeutic targeting.
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