AnkyrinG Is Required for Clustering of Voltage-gated Na Channels at Axon Initial Segments and for Normal Action Potential Firing

Abstract

Voltage-gated sodium channels (NaCh) are colocalized with isoforms of the membrane-skeletal protein ankyrinG at axon initial segments, nodes of Ranvier, and postsynaptic folds of the mammalian neuromuscular junction. The role of ankyrinG in directing NaCh localization to axon initial segments was evaluated by region-specific knockout of ankyrinG in the mouse cerebellum. Mutant mice exhibited a progressive ataxia beginning around postnatal day P16 and subsequent loss of Purkinje neurons. In mutant mouse cerebella, NaCh were absent from axon initial segments of granule cell neurons, and Purkinje cells showed deficiencies in their ability to initiate action potentials and support rapid, repetitive firing. Neurofascin, a member of the L1CAM family of ankyrin-binding cell adhesion molecules, also exhibited impaired localization to initial segments of Purkinje cell neurons. These results demonstrate that ankyrinG is essential for clustering NaCh and neurofascin at axon initial segments and is required for physiological levels of sodium channel activity.

ELF a β-spectrin is a neuronal precursor cell marker in developing mammalian brain; structure and organization of the elf/β-G spectrin gene

“…These considerations combined with the distinct NH2-terminal amino acid sequences for ELF and mouse brain b-G, suggest the possibility of two classes of b-G spectrin transcripts, each with distinct promoter elements. Similar studies have been shown for human ankyrin-1 (ANK-1) and Ankyrin G , spectrin binding proteins, transcripts of the latter being selectively expressed in brain and kidney (Gallagher et al, 1997(Gallagher et al, , 1999Zhou et al, 1998). A multitude of factors are responsible for diverse functions of spectrins.…”

“…In support of this are recent studies of ankyrin B mutants that exhibit hypoplasia of the corpus callosum and pyramidal tracts, dilated ventricles, extensive degeneration of the optic nerve, and die by postnatal day 21 (Scotland et al, 1998). Ankyrin G is required for clustering sodium channel (Nach) (Srinivasan et al, 1992) and neurofascin at axon initial segments and for physiological levels of voltage gated sodium channel activity Zhou et al, 1998). Similarly to ELF, ankyrin G is confined to initial segments of axons of granule cells as well as purkinje neurons.…”

Voltage-Gated Sodium Channels and AnkyrinG Occupy a Different Postsynaptic Domain from Acetylcholine Receptors from an Early Stage of Neuromuscular Junction Maturation in Rats

“…In mutant ankyrin-deficient neurons, there is an abnormal distribution of CAMs, ␤-spectrin, and Na V 1s and an inability to generate action potentials (Zhou et al, 1998;Jenkins and Bennett, 2001). This suggests that an as yet unidentified ankyrinG receptor recruits ankyrinG to the AIS as the first step in Na V 1 clustering.…”

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

“…4b). Given that previous studies provided direct evidence for a physiological role of ankG in the clustering of voltage-gated sodium channels into the axon initial segment 35 , we investigated whether Ab treatment could interfere with the ability of the neuron to fire action potentials upon injection of current at the soma in whole-cell patch-clamp recordings. Examination of action potential profile revealed a marked increase of the spike threshold (defined by the membrane potential at which dV/dt of the spike crossed 15-20 mV ms À 1 ) for Ab-treated neurons compared with the control ones ( Fig.…”