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

Shalomov, B.; Papa-Dmitrieva, I.; Keren Raifman, T.; Weiss, S.; De Martino, F.; Gali-Sayag, A.; Hirsch, J. A.; Taglialatela, M.; Barrese, V.; Zuehlke, K.; Klussmann, E.; Greenwood, I.; Lotan, I.; Dascal, N.

doi:10.64898/2026.09.15.751787

bioRxiv · 10.64898/2026.09.15.751787

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

Shalomov, B.·Papa-Dmitrieva, I.·Keren Raifman, T.·Weiss, S.·De Martino, F.·Gali-Sayag, A.·Hirsch, J. A.·Taglialatela, M.·Barrese, V.·Zuehlke, K.·Klussmann, E.·Greenwood, I.·Lotan, I.·Dascal, N.

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Abstract

The M-current, generated by voltage gated KV7.2/7.3 channels, sets the threshold for neuronal action potential and acts as a key brake on repetitive firing. The M-current is tightly regulated by signaling molecules, such as calmodulin and phosphatidylinositol-4,5-bisphosphate (PIP2). Here, we show that coexpression of the ubiquitous subunit dimer of heterotrimeric G-proteins, G{beta}{gamma}, with KV7.2/7.3 in Xenopus laevis oocytes doubles maximal M-current. This regulation requires free, prenylated, membrane-associated G{beta}{gamma} and operates via two distinct mechanisms: 1) increasing plasma membrane (PM) channel density and 2) stabilizing KV7.2/7.3-PIP2 coupling. Conversely, G{beta}{gamma} scavengers reduce basal KV7.2/7.3 current and weaken PIP2 coupling. Proximity ligation assays confirm colocalization of G{beta}{gamma} and KV7.2/7.3 in the PM. Peptide array and AlphaFold modeling identify putative interaction sites on the channel cytoplasmic domain. Finally, the disease-causing G{beta}1 variant I80N abolished G{beta}{gamma}-induced M-current potentiation. Together, these findings establish G{beta}{gamma} as a significant physiological regulator and potential site of vulnerability in neuronal M-current function.

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Shalomov, B., Papa-Dmitrieva, I., Keren Raifman, T., Weiss, S., De Martino, F., Gali-Sayag, A., Hirsch, J. A., Taglialatela, M., Barrese, V., Zuehlke, K., Klussmann, E., Greenwood, I., Lotan, I., Dascal, N.. 2026-09-21. Gβγ dually regulates the M current via increased channel surface expression and PIP2 sensitivity. https://doi.org/10.64898/2026.09.15.751787

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