The Institute of Physics of the Chinese Academy of Sciences and others have discovered a new mechanism for rapid inactivation of sodium channels

On May 17, Jiang Daohua, a researcher at the Institute of Physics of the Chinese Academy of Sciences, Gong Jianke, a professor at Huazhong University of Science and Technology, and Huang Zhuo, a professor at peking university school of medicine, published an article online in Nature Communications, which for the first time found that there is an N-type rapid inactivation gating mechanism in the voltage-gated sodium ion channel NaVEh, which is completely different from the classic IFM motif-mediated rapid inactivation in the sodium channels of higher animals. NaVEh’s N-terminal spiral is inserted directly and blocks the activated central cavity portal hole, allowing it to achieve rapid inactivation. Structural evidence is provided to understand the functional similarities, structural diversity, and evolutionary conservatism of sodium channels (see figure below).

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Diagram of rapid inactivation mode of two sodium channels Courtesy of interview subjects

Voltage-gated sodium channels are responsible for initiating and propagating action potentials, which play a vital role in a variety of physiological processes such as higher biological nerve signaling, muscle contraction, and neurotransmitter release. Activation and inactivation of channels are essential for regulating cellular excitability, and dysfunction of either process can lead to abnormal channel function and can lead to life-threatening diseases.

Sodium channels in higher animals typically deactivate rapidly within a few milliseconds. Current eukaryotic sodium channel structural studies have shown that a conservative IFM motif acts as a hydrophobic latch that closes the activation gate in an allosteric manner. In contrast, homologous tetramer protonuclear sodium channels lack IFM motifs and do not have a mechanism of rapid inactivation, but instead have slow inactivation within hundreds of milliseconds. From an evolutionary perspective, a link is missing between the slow inactivation of the prokaryotic sodium channel and the rapid inactivation of the eukaryotic sodium channel.

Eukaryotic single-celled organism Emiliania huxleyi is a species of marine plant Cobbleus, which is vital to marine ecology and is highly correlated with climate change. Its homologous tetramer sodium channel (NaVEh) lacks the IFM motif of the iconic element of rapid inactivation, but has a rapid inactivation characteristic similar to that of human sodium channels in the millisecond level. This means that eukaryotes may have a mechanism of rapid inactivation that differs from that of IFM motifs. So how do these sodium channels achieve rapid inactivation? What are the untold mysteries of the evolution of sodium channels?

Jiang Daohua introduced that the researchers used single-particle cryo-EM technology to analyze the structure of the Eukaryote cobblestone algae sodium channel NaVEh protein resolution of 2.8 angstroms, revealing for the first time the presence of N-type fast inactivation gating mechanism in sodium channels, which is completely different from the fast inactivation mediated by IFM motifs in higher animal sodium channels. NaVEh’s N-terminal spiral inserts and blocks the central cavity portal that has been activated, allowing it to achieve rapid inactivation.

Further studies have shown that rapid inactivation occurs due to the various electrostatic interactions between the N-terminal spiral and the central cavity portal hole. N-terminal helix deletion or mutation of positively charged amino acids to negatively charged amino acids can cause Rapid inactivation and loss of NaVEh. When the synthesized N-helix polypeptide is backcompiled, the rapid inactivation of NaVEh can be restored.

In addition, the authors found that, significantly different from mammalian sodium channels, NaVEh recovered from rapid inactivation about 157 times slower than in humans NaV1.7. The stronger binding interaction of the N-helix causes the energy barrier released from the open gate to release the N-helix will be much higher than the energy barrier released by the IFM-motif from its receptor site, which is the main cause of its slow recovery rate after inactivation.

“This study contributes to a better understanding of the conservatism of sodium channels in evolution.” Jiang Daohua told China Science Daily, “Rapid inactivation of NaVEh may be important for single-celled phytoplankton to tolerate high concentrations of sodium in living environments, but its slow recovery of inactivation may prevent this mechanism from being used in higher animals that require high-frequency electrical signals; thus allowing higher animals to choose in evolutionary rapid inactivation mediated rapid inactivation by IFM-motifiction characterized by rapid inactivation and rapid recovery.” (Source: China Science Daily Liu Runan)

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