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EDITORIAL FOCUS
) or spreads Ca2+ entry over longer periods of time compared with activity in mature cells (Dallman et al. 2000). Small, slow K+ currents also serve to increase the excitability of immature neurons, especially in response to slow depolarizing stimuli (Greaves et al. 1996). It is during the stages when outward K+ currents are small and slow that many developing neurons and muscle cells are spontaneously active and when activity-dependent developmental programs are initiated. The increased density and activation rate of outward K+ currents is thus a key event that terminates early periods of spontaneous activity and transforms the firing properties of many cells to their mature state. In some cells, such as inner hair cells of the cochlea, this transformation is particularly dramatic in that the ability to generate action potentials is lost entirely (Fuchs and Sokolowski 1990; Marcotti et al. 2003a, b) even as voltage-gated Ca2+ currents and Ca2+ entry are retained. It is significant that in many cells, either the developmental increase in K+ current density or the speeding of activation, or both, depend on the very spontaneous activity that they help to terminate (Bixby and Spitzer 1984; Dallman et al. 1998; Desarmenien and Spitzer 1991; Linsdell and Moody 1994, 1995).
During development, Xenopus spinal neurons show a large increase in the density of delayed K+ currents. This, along with a pronounced speeding of K+ current activation, markedly shortens the action potential over the course of only 24 h (Spitzer and Baccaglini 1976). This action potential shortening helps to terminate a period of spontaneous, activity-dependent [Ca2+]i transients that are essential for the normal development of neuron morphology, physiology, and transmitter phenotype (Desarmenien and Spitzer 1991; Gu and Spitzer 1995; Watt et al. 2000). After this period of increasing K+ current density, these neurons maintain a stable K+ currents despite the continuation of many further events of their development, such as synapse formation.
In an article in this issue, Blaine et al. (p. 3446–3454), using these Xenopus neurons, present some very interesting observations that shed light on the complex question of how developing nerve cells make this switch between a critically timed developmental increase in outward K+ current density and a later maintenance of the mature density. By injecting RNA for specific types of delayed K+ channels into one blastomere of a two-cell stage Xenopus embryo and measuring K+ current density in the neurons that develop from that blastomere, they have shown that the ability of excess channel transcripts to increase current density differs markedly among delayed K+ channel types and at different stages of development. Excess Kv1.1 and Kv2.1 transcripts increase current density in both immature and mature neurons, whereas excess Kv2.2 transcript can only increase current density in immature neurons. By using chimeric transcripts between Kv2.1 and Kv2.2, they further showed that a carboxy tail domain, which they term proxC, determines this behavior. Chimerae lacking proxC increased K+ current density in mature neurons when overexpressed, whereas those containing proxC did not, independent of the donor of the transmembrane domains and hence of the biophysical properties of the expressed channel. These results show that the developmental switch in how K+ current density is regulated could be accomplished in part by changing the identity of the K+ channel subunits expressed rather than by changing transcription or RNA turnover rates. This places in a developmental context a body of earlier work showing that different K+ channel family members differ in the efficiency with which they are trafficked to the plasma membrane (Li et al. 2000; Manganis and Trimmer 2000; Manganis et al. 2001).
We can think of developing neurons moving through at least three states: an early period of immature channel expression, a transition period of changing levels and types of channel expression, and a mature state where plasticity centers around some kind of set-point of channel densities and firing behavior. Because the transition state in many cells involves a change in the identity of the K+ channels (and many other channels) that are expressed, much attention has been paid to how the biophysical properties of the immature and mature K+ channels might be optimized to their different functions. The results of Blaine et al. show that we also need to think of how channel subtypes might differ in their intracellular trafficking at different stages of development and how the set point for total functional K+ channel density might be established during development by controlling the K+ channel subunit composition that contributes to the total current at different developmental stages.
Department of Biology, University of Washington, Seattle, Washington 98115
Address for reprint requests and other correspondence: W. J. Moody, Department of Biology, University of Washington, Seattle, WA 98115 (E-mail: profbill{at}u.washington.edu).
REFERENCES
Bixby JL and Spitzer NC. Early differentiation of vertebrate spinal neurons in the absence of voltage-dependent Ca2+ and Na+ influx. Dev Biol 108: 89–96, 1984.
Blaine JT, Taylor AD, and Ribera AB. The carboxyl tail region of the Kv2.2 subunit mediates novel developments of channel density. J Neurophsyiol 92: 3446–3454, 2004.
Dallman JE, Davis AK, and Moody WJ. Spontaneous activity regulates calcium-dependent K+ current expression in developing ascidian muscle. J Physiol 511: 683–693, 1998.
Dallman JE, Dorman J, and Moody WJ. Action potential waveform voltage clamp reveals the significance of the patterns of ion channel development in ascidian muscle. J Physiol 524: 375–386, 2000.
Desarmenien MG and Spitzer NC. Role of calcium and protein kinase C in development of the delayed rectifier potassium current in Xenopus spinal neurons. Neuron 7: 797–805, 1991.[CrossRef][ISI][Medline]
Fuchs P and Sokolowski BH. The acquisition during development of Ca-activated potassium currents by cochlear hair cells of the chick. Proc R Soc Lond B Biol Sci 241: 122–126, 1990.[Medline]
Greaves AA, Davis AK, Dallman JE, and Moody WJ. Development of ionic currents in the muscle lineage of the ascidian Boltenia villosa. J Physiol 497: 39–52, 1996.[ISI][Medline]
Gu X and Spitzer NC. Distinct aspects of neuronal differentiation encoded by frequency of spontaneous Ca2+ transients. Nature 375: 784–787, 1995.[CrossRef][Medline]
Jones SM and Ribera AB. Overexpression of a potassium channel gene perturbs neural differentiation. J Neurosci 14: 2789–2799, 1994.[Abstract]
Li D, Takomoto K, and Levitan ES. Surface expression of Kv1 channels is governed by a C-terminal motif. J Biol Chem 275: 11597–11602, 2000.
Linsdell P and Moody WJ. Na+ channel mis-expression accelerates K+ channel development in embryonic Xenopus laevis skeletal muscle. J Physiol 480: 405–410, 1994.[ISI]
Linsdell P and Moody WJ. Electrical activity and calcium influx regulate ion channel development in embryonic Xenopus skeletal muscle. J Neurosci 15: 4507–4514, 1995.[Abstract]
Manganas LN and Trimmer JS. Subunit composition determines Kv1 potassium channel surface expression. J Biol Chem 275: 29685–29693, 2000.
Manganas LN, Wang Q, Scannevin RH, Antonucci DE, Rhodes KJ, and Trimmer JS. Identification of a trafficking determinant localized to the Kv1 potassium channel pore. Proc Nat Acad Sci USA 98: 14055–14059, 2001.
Marcotti W, Johnson SL, Holley MC, and Kros CJ. Developmental changes in the expression of potassium currents of embryonic, neonatal and mature mouse inner hair cells. J Physiol 549: 383–400, 2003a.
Marcotti W, Johnson SL, Rusch A, and Kros CJ. Sodium and calcium currents shape action potentials in immature mouse inner hair cells. J Physiol 552: 743–761, 2003b.
Spitzer NC and Baccaglini PI. Development of the action potential in embryo amphibian neurons in vivo. Brain Res 107: 610–616, 1976.[CrossRef][ISI][Medline]
Watt SD, Gu X, Smith RD, and Spitzer NC. Specific frequencies of spontaneous Ca2+ transients up-regulate GAC-67 transcripts in embryonic spinal neurons. Mol Cell Neurosci 16: 376–387, 2000.[CrossRef][ISI][Medline]
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