Navs

Question 1

How is the structure of Navs?

Answer 1

Nav channels belong to the voltage-gated ion channel (VGIC) superfamily. They usually comprise a core α subunit, which alone is sufficient for channel activities, and auxiliary β subunits (β1-β4) that aid in membrane localization and channel modulation.

The α subunit is a single polypeptide of approximately 2000 residues in length and folds into four homologous repeats (repeat I-IV).

Each repeat consists of six transmembrane helices (S1-S6), among which S5 and S6 from all four repeats constitute the ion-permeating pore domain (PD), and S1-S4 in each repeat form the flanking voltage-sensing domain (VSD). The sequences between S5 and S6 assemble into the extracellular loops (ECLs) and the ion selectivity filter (SF) .

Question 2

Which residues are responsible for the selectivity?

Answer 2

Four distinct residues, Asp/Glu/Lys/Ala (DEKA), located in the corresponding SF locus of each repeat, are responsible for sodium ion selectivity.

Question 3

Which motif is essential for the fast inactivation of Nav channels?

Answer 3

The III-IV linker contains the Ile/Phe/Met (IFM) motif, which is essential for the fast inactivation of Nav channels.

Mutagenesis of this hydrophobic cluster may abolish the fast inactivation completely.

Question 4

Which Nav subtypes of α subunits exist in humans?

And where are the subtypes expressed?

Answer 4

There are nine subtypes of Nav α subunits in human, designated Nav1.1-Nav1.9.

Nav1.1–Nav1.3 and Nav1.6
–> are prevailingly expressed in the central nervous system.

Nav1.4
–> skeletal muscles

Nav1.5
–> cardiac muscles

Nav1.7–Nav1.9
–> primarily function in the peripheral nervous system

Question 5

How is the working diagram of Nav channels?

Answer 5

The working diagram onsists of three primary states: resting, activated, and inactivated.

Under resting membrane potential, the Nav channels are non-conductive with a closed PD and the VSDs in the “down” conformation. In response to membrane depolarization, the S4 helices are driven toward the extracellular side to achieve the “up” conformations.

The motions of VSDs result in the opening of the PD, a process known as the electromechanical coupling.

Immediately after activation, the channel undergoes fast inactivation within 1 ~ 2 ms. Nav channels are released from the inactivated state to return to the resting state upon membrane hyperpolarization, ready for the next working cycle