Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance

Abstract

The intrinsic electrical characteristics of different types of neurons are shaped by the K⁺ channels they express. From among the more than 70 different K⁺ channel genes expressed in neurons, Kv3 family voltage-dependent K⁺ channels are uniquely associated with the ability of certain neurons to fire action potentials and to release neurotransmitter at high rates of up to 1,000 Hz. In general, the four Kv3 channels Kv3.1-Kv3.4 share the property of activating and deactivating rapidly at potentials more positive than other channels. Each Kv3 channel gene can generate multiple protein isoforms, which contribute to the high-frequency firing of neurons such as auditory brain stem neurons, fast-spiking GABAergic interneurons, and Purkinje cells of the cerebellum, and to regulation of neurotransmitter release at the terminals of many neurons. The different Kv3 channels have unique expression patterns and biophysical properties and are regulated in different ways by protein kinases. In this review, we cover the function, localization, and modulation of Kv3 channels and describe how levels and properties of the channels are altered by changes in ongoing neuronal activity. We also cover how the protein-protein interaction of these channels with other proteins affects neuronal functions, and how mutations or abnormal regulation of Kv3 channels are associated with neurological disorders such as ataxias, epilepsies, schizophrenia, and Alzheimer's disease.

FIGURE 1.

Schematic diagram of a Kv3.1 subunit, showing splice isoforms, location of a phosphorylation site for PKC, and sites for glycosylation. Right panel shows typical non-inactivating currents evoked by voltage-clamp pulses lasting 150 ms.

FIGURE 2.

Axon targeting of Kv3.1b. A: the axonal targeting motif is located in the COOH terminus immediately after the 6th membrane spanning segment S6. It carries a net positive charge of +7. Kv3.1 isoforms are aligned with three other Kv3 family channels. Conserved residues are highlighted in yellow. Numbers above the sequence indicate the positions of residues in Kv3.1a. Underlined residues are critical for axonal targeting. [From Xu et al. (251).] B: a diagram to illustrate the hypothesis on how the axonal targeting motif is regulated.

FIGURE 3.

Schematic diagram of a Kv3.2 subunit, showing splice isoforms, location of two phosphorylation sites for the cAMP-dependent protein kinase, and sites for glycosylation. Right panel shows typical non-inactivating currents evoked by voltage-clamp pulses lasting 800 ms.

FIGURE 4.

Schematic diagram of a Kv3.3 subunit, showing splice isoforms, location of NH₂-terminal phosphorylation sites for PKC, sites for glycosylation, and binding of Hax-1 to the cytoplasmic COOH-terminal domain. Right panel shows typical slowly inactivating currents evoked by voltage-clamp pulses lasting 500 ms.

FIGURE 5.

Schematic diagram of a Kv3.4 subunit and the ancillary subunit MiRP2, showing splice isoforms, location of phosphorylation sites for PKC on both proteins, and sites for glycosylation. Right panel shows typical rapidly inactivating currents evoked by voltage-clamp pulses lasting 900 ms.

FIGURE 6.

Effects of the activation of either PKC or PKA on the amplitude and inactivation kinetics of each of the four Kv3 family channels. The lowest panels show superimposed structures determined by NMR for the NH₂-terminal 30 amino acids of Kv3.4 without (left) and with (right) phosphorylation of serine 8. [From Antz et al. (12).]

FIGURE 7.

Kv3.1 currents recorded in CHO cells before and after internal dialysis with alkaline phosphatase. Current-voltages in the right panel show that dephosphorylation shifts voltage-dependent activation to negative potentials. [From Macica and Kaczmarek (147).]

FIGURE 8.

Zinc-dependent interactions of Kv3.1. A: locations of Zn²⁺-binding sites in the Kv3.1 protein. [From Gu et al. (87).] Relative lengths of NH₂- and COOH-terminal domains are not to scale. B: interaction of Kv3.1 tetramers with the kinesin I motor protein KIF5. [From Barry et al. (16).]

FIGURE 9.

Interactions of Kv3.3 with the actin cytoskeleton. A: effects of transfection of Kv3.3 into CHO cells on cell morphology and the actin cytoskeleton, and co-localization of actin with Kv3.3. B: effects of Hax-1 siRNA as well as agents that disrupt the Arp2/3-dependent cortical cytoskeleton on rate of inactivation of Kv3.3. [From Zhang et al. (261).]

FIGURE 10.

Deletion of Kv3 channels affects firing patterns. A: postsynaptic responses of MNTB neurons from wild-type and Kv3.1^−/− mice to repetitive stimulation at 300 Hz. [From Macica et al. (148).] B: effect of deletion of the Kv3.2 gene on the response of parvalbumin-expressing interneuron in deep cortical layers to a sustained depolarizing current. [From Lau et al. (129).] C: loss of Kv3.3 eliminates spikelets during a complex spike in cerebellar Purkinje cells. [From Zagha et al. (256).] D: suppression of Kv3.4 using siRNA broadens the action potentials of dorsal root ganglion cells. [From Ritter et al. (195).]