Trends in Neurosciences
ReviewKv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing
Section snippets
Molecular characteristics of Kv3 subfamily members
Both rodents and humans possess four Kv3 genes: Kv3.1, Kv3.2, Kv3.3 and Kv3.4 (6, 7). All four Kv3 genes generate multiple protein isoforms by alternative splicing, which produces versions with different intracellular C-terminal sequences. There are now 13 different Kv3 proteins known in mammals (Kv3.1a–Kv3.1b, Kv3.2a–Kv3.2d, Kv3.3a–Kv3.3d and Kv3.4a–Kv3.4c), yet the currents expressed in heterologous expression systems by the spliced isoforms of each Kv3 gene are virtually indistinguishable.
Kv3 proteins express voltage-gated channels with unusual properties in heterologous expression systems and in native cells
Chinese hamster ovary (CHO) cells transfected with cDNAs of transcripts from each of the four Kv3 genes (Kv3.1b, Kv3.2a, Kv3.3d and Kv3.4a) have large voltage-dependent K+ currents with similar voltage dependencies (Fig. 1a,b) 6, 7. The currents become apparent when the membrane is depolarized to potentials more positive than approximately −20 mV, which is more depolarized than any other known mammalian voltage-gated K+ channel by at least 10–20 mV (Ref. 16). Another crucial property of the
Kv3 currents are activated specifically during action potential repolarization
The electrophysiological properties of Kv3 channels suggest a specific role in action potential repolarization 6, 7, 11, 15, 18, 33, 34, 35, 36, 37, 38. Given their voltage dependence, it is unlikely that Kv3 channels will be significantly activated other than during action potentials, and only once these have reached their peak. Confirmation of this hypothesis has come from recording currents from HEK293 cells transfected with Kv3.1 or Kv3.2 cDNAs voltage clamped to a waveform in the shape of
Kv3 channels are prominently expressed in neurons that fire at high frequency
In rodents, three of the four known Kv3 genes (Kv3.1–Kv3.3) are prominently expressed in the CNS. Kv3.4 transcripts are abundant in skeletal muscle and sympathetic neurons, but are only weakly expressed in a few neuronal types in the brain, often in neurons that also express other Kv3 genes 6, 15, 19, 44, 45. However, as a single Kv3.4 subunit is capable of enabling fast inactivating properties to a Kv3 tetrameric channel 15 (Fig. 1c), they might be important functional determinants, even when
Kv3 channels are necessary for high-frequency repetitive firing
How do the unique electrophysiological properties of Kv3 channels lend themselves to facilitating high frequency repetitive firing? As discussed, neurons can use large numbers of Kv3 channels to accelerate action potential repolarization with a minimum risk of compromising action potential generation (Box 1). By increasing the rate of spike repolarization and thus keeping action potentials short, Kv3 currents can reduce the amount of Na+ channel inactivation occurring during the action
Modulation of Kv3 K+ channels
In numerous systems, modulation of voltage-gated channels by kinases and phosphatases provides additional mechanisms to dynamically regulate membrane properties 60, 61, 62, 63. Channels formed by Kv3 subfamily members are targets for such modulation 11, 37, 49, 64, 65, 69. Given the dominant functional role of Kv3 channels in some neurons, their phosphorylated state could have profound influences on the physiological properties of the cell and the network to which it is connected (Fig. 5).
Kv3.2
Concluding remarks
Together, the experimental data and computer modeling support the idea that the activation range and fast deactivation kinetics of Kv3 channels function specifically to enable neurons to fire repetitively at high frequencies 5, 6, 23, 24, 40, 43, 49, 69. Kv3 channels might have been a common solution in vertebrates to the problems imposed by high-frequency repetitive firing, as they appear to be present in most neurons that can fire repetitively at high frequencies. It remains to be seen
Acknowledgements
We thank our colleagues E. Phillips-Tansey, J. Du, M. Atzori, L. Zhang, C. Leonard, A. Erisir, D. Contreras, C. Kentros, H. Moreno, E. Vega, Y. Amarillo, M. Nadal, M. Saganich, A. Ozaita, A. Chow, P. Rhodes and D. Lau for their contributions to this work. We also thank J. Rae for Kv3.3d cDNA. Our research is supported by NIH Grants NS30989 and NS35215, and NSF grant IBN 0078297 to B.R.
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