The sorting receptor Rer1 controls Purkinje cell function via voltage gated sodium channels

Christina Valkova,Andreas Krämer,Christian A Hübner,Christoph Kaether,Lutz Liebmann

doi:10.1038/srep41248

Abstract

Rer1 is a sorting receptor in the early secretory pathway that controls the assembly and the cell surface transport of selected multimeric membrane protein complexes. Mice with a Purkinje cell (PC) specific deletion of Rer1 showed normal polarization and differentiation of PCs and normal development of the cerebellum. However, PC-specific loss of Rer1 led to age-dependent motor deficits in beam walk, ladder climbing and gait. Analysis of brain sections revealed a specific degeneration of PCs in the anterior cerebellar lobe in old animals. Electrophysiological recordings demonstrated severe deficits in spontaneous action potential generation. Measurements of resurgent currents indicated decreased surface densities of voltage-gated sodium channels (Nav), but not changes in individual channels. Analysis of mice with a whole brain Rer1-deletion demonstrated a strong down-regulation of Nav1.6 and 1.1 in the absence of Rer1, whereas protein levels of the related Cav2.1 and of Kv3.3 and 7.2 channels were not affected. The data suggest that Rer1 controls the assembly and transport of Nav1.1 and 1.6, the principal sodium channels responsible for recurrent firing, in PCs.

Highlights

Motor coordination in mammals is controlled by the cerebellum, a part of the hindbrain
An indicator for proper development of Purkinje cell (PC) is the thickness of the molecular layer, because this is primarily determined by the dendritic tree of PCs22,23
For generation of the resurgent Na+ current that is essential for action potentials in PCs, a specific voltage-dependent Na-channel, the Nav1.6, with its multiple transmembrane domains (TM) domains needs to be co-translationally inserted into the ER, properly folded, assembled with the correct β-subunit(s), transported through the Golgi, sorted into vesicles destined for the axon initial segment (AIS), inserted there, and fulfill its function as an ion channel

Summary

Introduction

Motor coordination in mammals is controlled by the cerebellum, a part of the hindbrain. Nav1.6, encoded by the SCN8A gene, constitutes the pore-forming large α-subunit and associates with a β2/β4 subunit and a β1/β3 subunit[3] Another important sodium channel at the AIS of Purkinje cells is Nav1.1 (encoded by SCN1A)[4], critically involved in PC excitability[5]. Both Nav1.1 and 1.6 are large, glycosylated membrane proteins with four domains, each composed of 6 transmembrane domains (TM), whereas the β-subunits are single-pass TM proteins[6]. How Navs assemble, and which mechanisms control and guide their transport through the secretory pathway is largely unknown. The underlying molecular cause is a reduction in Nav1.1 and 1.6 protein levels, suggesting that Rer[1] is involved in the quality control of Nav ion channels

Methods

Results

Conclusion