Gβγ dually regulates the M current via increased channel surface expression and PIP2 sensitivity
- 1Tel Aviv University
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.
Related
- Potassium inward rectifier channel subfamily J member 11 mRNA expression in glioma and its significance in predicting prognosis and chemotherapy sensitivity
- Increased expression of hPGDS‑PGD2 in patients with eosinophilic chronic rhinosinusitis with nasal polyps
- Colonic LRRK2 expression is increased in Crohn's disease but not in Parkinson's disease and idiopathic RBD
- An enhancer-like region regulates hrp3 promoter stage-specific gene expression in the human malaria parasite Plasmodium falciparum
- Prostaglandin-Endoperoxide Synthase 2 (PTGS2) Expression Is Increased in Chronic Asymptomatic Orchitis in the Dog.
BibTeX
@misc{shalomov2026gβγ,
title = {{Gβγ dually regulates the M current via increased channel surface expression and PIP2 sensitivity}},
author = {B. Shalomov and I. Papa-Dmitrieva and T. Keren Raifman and S. Weiss and F. De Martino and A. Gali-Sayag and J. A. Hirsch and M. Taglialatela and V. Barrese and K. Zuehlke and E. Klussmann and I. Greenwood and I. Lotan and N. Dascal},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751787},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751787v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Gβγ dually regulates the M current via increased channel surface expression and PIP2 sensitivity
AU - B. Shalomov
AU - I. Papa-Dmitrieva
AU - T. Keren Raifman
AU - S. Weiss
AU - F. De Martino
AU - A. Gali-Sayag
AU - J. A. Hirsch
AU - M. Taglialatela
AU - V. Barrese
AU - K. Zuehlke
AU - E. Klussmann
AU - I. Greenwood
AU - I. Lotan
AU - N. Dascal
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751787
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751787v1
AB - 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.
ER -