Cyclic nucleotide–gated (CNG) channels are essential mediators of visual and olfactory signal transduction, and their activity is strongly influenced by membrane-associated regulators. This work investigates two recently identified modulators of olfactory CNG channels: membrane lipids and phosphoinositide‑3,4,5‑trisphosphate (PIP₃). Cholesterol depletion reduced channel sensitivity to cyclic nucleotides, although this effect appeared independent of lipid raft association. In parallel, PIP₃ was shown to potently inhibit olfactory CNG channels through an N‑terminal region of the CNGA2 subunit, interfering with intersubunit regulatory interactions. These findings reveal lipid-dependent mechanisms that finely tune olfactory CNG channel function.
