Effects of K⁺ Channel Blockers on Developing Rat Myelinated CNS Axons: Identification of Four Types of K⁺Channels

Abstract

Devaux, Jerome, Maurice Gola, Guy Jacquet, and Marcel Crest. Effects of K ϩ channel blockers on developing rat myelinated CNS axons: identification of four types of K ϩ channels. J Neurophysiol 87: 1376 -1385, 2002; 10.1152/jn.00646.2001. Four blockers of voltagegated potassium channels (Kv channels) were tested on the compound action potentials (CAPs) of rat optic nerves in an attempt to determine the regulation of Kv channel expression during the process of myelination. Before myelination occurred, 4-aminopyridine (4-AP) increased the amplitude, duration, and refractory period of the CAPs. On the basis of their pharmacological sensitivity, 4-AP-sensitive channels were divided in two groups, the one sensitive to kaliotoxin (KTX), dendrotoxin-I (DTX-I), and 4-AP, and the other sensitive only to 4-AP. In addition, tetraethylammonium chloride (TEA) applied alone broadened the CAPs. At the onset of myelination, DTX-I induced a more pronounced effect than KTX; this indicates that a fourth group of channels sensitive to 4-AP and DTX-I but insensitive to KTX had developed. The effects of KTX and DTX-I gradually disappeared during the period of myelination. Electron microscope findings showed that the disappearance of these effects was correlated with the ongoing process of myelination. This was confirmed by the fact that DTX-I and KTX enlarged the CAPs of demyelinated adult optic nerves. These results show that KTX-and DTX-sensitive channels are sequestrated in paranodal regions. During the process of myelination, KTX had less pronounced effects than DTX-I on demyelinated nerves, which suggests that the density of the KTX-sensitive channels decreased during this process. By contrast, 4-AP increased the amplitude, duration, and refractory period of the CAPs at all the ages tested and to a greater extent than KTX and DTX-I. The effects of TEA alone also gradually disappeared during this period. However, effects of TEA on CAPs were observed when this substance was applied after 4-AP to the adult optic nerve; this shows that TEAsensitive channels are not masked by the myelin sheath. In conclusion, the process of myelination seems to play an important part in the regulation and setting of Kv channels in optic nerve axons. I N T R O D U C T I O NPeripheral myelinated fibers have been found to contain three main voltage-gated potassium channels (Kv channels): a Kv channel sensitive to tetraethyl-ammonium chloride (TEA) that is present throughout the axons, and two channels sensitive to 4-aminopyridine (4-AP), that are distinguishable by their differential sensitivity to dendrotoxin and are located in internodal and paranodal regions (for review, see Vogel and Schwarz 1995). Although the molecular composition of channels sensitive to TEA or to 4-AP has not yet been determined, the channels sensitive to DTX are assumed to result from the association of the Kv1.1 and Kv1.2 ␣ subunits (Reid et al. 1999; Stuhmer et al. 1989). These subunits have been detected in juxtaparanodal regions of peripheral myelinated fibers (Arroyo et ...

Genetic and Physiological Evidence That Oligodendrocyte Gap Junctions Contribute to Spatial Buffering of Potassium Released during Neuronal Activity

“…In contrast, myelination in rodent optic nerve is accompanied by a concentration of the voltagegated K ϩ channels KCNQ2 and KCNQ3 into the nodal axolemma (Devaux et al, 2004;Pan et al, 2006) and Kv1.1 and Kv1.2 into the juxtaparanodal axolemma Vabnick and Shrager, 1998). Furthermore, myelination is accompanied by dramatic decreases in the amount of extracellular K ϩ detected during neuronal activity (Connors et al, 1982), in the extracellular volume (Ransom et al, 1985) and in the effects of K ϩ channel blockers (Devaux et al, 2002). Changes in K ϩ channel distribution are likely in part responsible for those physiological changes.…”

“…The vacuoles in Cx32/Cx47 dKO (Kir4.1 ϩ/ϩ ) mice are mostly in the periaxonal space, between the axon and the myelin sheath. Because reflexive coupling should be strongly affected, these vacuoles could result from an inability to redistribute the K ϩ released through Shaker-type Kv1.1 and Kv1.2 channels into the periaxonal space Devaux et al, 2002 ]. This model is consistent with the known localization of Cx32 and Cx47 at both paranodal regions and perikarya (Menichella et al, 2003;Kamasawa et al, 2005) and Kir4.1 predominantly in oligodendrocyte perikarya and astrocyte end feet (Kalsi et al, 2004).…”

KCNQ2 Is a Nodal K+Channel

“…During the experiment, the nerves were kept in ACSF at 37°C in a 95% O 2 -5% CO 2 atmosphere perfused at a flow rate of 1-2 ml/min. For optic nerves, suction electrodes were used for recording of compound action potentials (CAPs) (Devaux et al, 2002). For sciatic nerves, a threecompartment recording chamber was used; the distal end was stimulated supramaximally (40 sec duration) through two electrodes isolated with Vaseline, and recordings were performed at the proximal end.…”

Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA

“…Indeed, patients with mutation in the KCNA1 gene, which encodes Kv1.1, present myokymic syndromes (Browne et al, 1994;Eunson et al, 2000). However, in the CNS, Kv3.1b is present at nodes and may participate to the repolarization (Devaux et al, 2002(Devaux et al, , 2003.…”