Gβγ dually regulates the M current via increased channel surface expression and PIP2 sensitivity

The M-current, produced by voltage-gated KV7.2/7.3 channels, influences neuronal action potential thresholds and acts as a crucial inhibitor for repetitive firing. This current's regulation is influenced by signaling molecules, including calmodulin and phosphatidylinositol-4,5-bisphosphate (PIP2). Researchers have discovered that the coexpression of the Gβγ subunit dimer with KV7.2/7.3 in Xenopus laevis oocytes results in a doubling of the maximum M-current.

This regulation is achieved through two independent mechanisms: increasing the number of channel proteins on the plasma membrane and enhancing the coupling between KV7.2/7.3 and PIP2. On the other hand, scavengers of Gβγ reduce the basal KV7.2/7.3 current and weaken the PIP2 coupling. Proximity ligation assays confirm the colocalization of Gβγ and KV7.2/7.3 at the plasma membrane.

Peptide array and AlphaFold modeling have identified potential interaction sites on the channel's cytoplasmic domain. Additionally, a disease-causing Gβ1 variant, I80N, prevents the Gβγ-induced potentiation of M-current. These findings underscore the significant physiological role of Gβγ as a regulator and a potential vulnerability site in neuronal M-current function.