Paralemmin-2 is a membrane-anchored cytoskeletal constituent of Axon Initial Segments and nodes of Ranvier

The axon initial segment (AIS) and nodes of Ranvier (NoR) are critical for the initiation and transmission of action potentials. These structures share similarities in their molecular organization and assembly processes, which converge on the membrane-associated periodic skeleton (MPS). Researchers have now discovered that Paralemmin-2 (Palm2) is a constituent of both the AIS and NoR.

When Palm2 is depleted, the AIS becomes shorter and neuronal excitability is reduced. In the AIS, endogenous Palm2 is non-periodic, but when Palm2 is overexpressed, it binds to the MPS, localizes to actin rings, and decreases the abundance and periodicity of {beta}IV-spectrin. In the NoR of the central and peripheral nervous systems, Palm2 is found in distinct subdomains - nodal or paranodal, respectively.

Palm2 interacts with the deubiquitinase USP7, suggesting a role for paralemmins in proteostasis at the MPS. The complementary localizations of Palm2 and its homolog Palm1 at the AIS/NoR or axon shafts mirror the distributions of {beta}-spectrin and ankyrin isoforms in these axonal compartments. The researchers propose that Palm2 regulates the submembrane cytoskeleton and its membrane attachment, contributing to the assembly, function, and remodeling of both the AIS and NoR.