When protein A regulates protein B, we usually assume it's because A binds to B. But biology is rarely that simple. A study in the Journal of Clinical Investigation shows that FGF13, known to regulate sodium channels in the heart, works primarily through an unexpected mechanism: altering local membrane cholesterol distribution.
The Channel and Its Regulator
NaV1.5 is the main sodium channel in heart muscle cells, essential for the electrical signals that coordinate heartbeats. FGF13 (a member of the fibroblast growth factor homologous factor family) binds to NaV1.5's C-terminus and modulates channel function. Mutations disrupting this interaction cause arrhythmias.
But the researchers made a structurally-guided mutant FGF13 that can't bind NaV1.5. Surprisingly, this binding-incompetent mutant still regulated the channel's steady-state inactivation - the canonical effect attributed to FGF13.
It's About Cholesterol
Instead of direct binding, FGF13 regulates NaV1.5 through effects on accessible membrane cholesterol. In cardiomyocytes, cholesterol is polarized - concentrated at the intercalated disc (ID) where cells connect and where most sodium channels localize.
Deleting FGF13 eliminated this polarized cholesterol distribution and caused loss of sodium channels from the ID. The cholesterol mechanism explained both channel regulation and the previously described stabilization of sodium currents at elevated temperatures.
Rewriting the Rules
This changes the canonical model of how auxiliary subunits regulate channels. It's not just about binding and direct conformational effects - auxiliary proteins can work through broader cellular mechanisms that indirectly affect the channels they regulate.
The finding also has clinical implications. If cholesterol distribution affects sodium channel function, lipid metabolism could influence arrhythmia risk in ways not previously appreciated.
Reference: Gade AR, et al. (2025). The NaV1.5 auxiliary subunit FGF13 modulates channels by regulating membrane cholesterol independent of channel binding. Journal of Clinical Investigation. doi: 10.1172/JCI191773 | PMID: 40794434
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.