Functional specialization of the axon initial segment by isoform-specific sodium channel targeting

Voltage-dependent sodium channels cluster at high density at axon initial segments, where propagating action potentials are thought to arise, and at nodes of Ranvier. Here, we show that the sodium channel Na(v)1.6 is precisely localized at initial segments of retinal ganglion cells (RGCs), whereas a different isoform, Na(v)1.2, is found in the neighboring unmyelinated axon. During development, initial segments first expressed Na(v)1.2, and Na(v)1.6 appeared later, approximately in parallel with the onset of repetitive RGC firing. In Shiverer mice, Na(v)1.6 localization at the initial segment was unaffected, although Na(v)1.6 expression was severely disrupted in the aberrantly myelinated optic nerve. Targeting or retention of Na(v)1.6 requires molecular interactions that normally occur only at initial segments and nodes of Ranvier. Expression at nodes but not initial segments exhibits an additional requirement for intact myelination. Because of their high density at the initial segment, Na(v)1.6 channels may be crucial in determining neuronal firing properties.