Determinants of excitability at transition zones in Kv1.1-deficient myelinated nerves

This study examines the role of K channel segregation and fiber geometry at transition zones of mammalian nerve terminals in the peripheral nervous sy stem. Mutant mice that are deficient in Kv1.1, a fast Shaker K channel norm ally localized beneath the myelin sheath, display three types of cooling-in duced abnormal hyperexcitability localized to regions before the transition zones of myelinated nerves. The first type is stimulus-evoked nerve backfi ring that is absent at birth, peaks at postnatal day 17 (P17), and subsides in adults. The second type is spontaneous activity that has a more delayed onset, peaks at P30, and also disappears in older mice (>P60). TEA greatly amplifies this spontaneous activity with an effective dosage of similar to 0.7 mM, and can induce its reappearance in older mutant mice (>P100). Thes e first two types of hyperexcitability occur only in homozygous mutants tha t are completely devoid of Kv1.1. The third type occurs in heterozygotes an d represents a synergism between a TEA-sensitive channel and Kv1.1. Heteroz ygotes ex; posed to TEA display no overt phenotype until a single stimulati on is given, which is then followed by an indefinite phase of repetitive di scharge. Computer modeling suggests that the excitability of the transition zone near the nerve terminal has at least two major determinants: the pret erminal internodal shortening and axonal slow K channels. We suggest that v ariations in fiber geometry create sites of inherent instability that is no rmally stabilized by a synergism between myelin-concealed Kv1.1 and a slow, TEA-sensitive K channel.