Voltage-gated potassium channels and the diversity of electrical signalling

Abstract

Since Hodgkin and Huxley discovered the potassium current that underlies the falling phase of action potentials in the squid giant axon, the diversity of voltage-gated potassium (Kv) channels has been manifested in multiple ways. The large and extended potassium channel family is evolutionarily conserved molecularly and functionally. Alternative splicing and RNA editing of Kv channel genes diversify the channel property and expression level. The mix-and-match of subunits in a Kv channel that contains four similar or identical pore-forming subunits and additional auxiliary subunits further diversify Kv channels. Moreover, targeting of different Kv channels to specific subcellular compartments and local translation of Kv channel mRNA in neuronal processes diversify axonal and dendritic action potentials and influence how synaptic plasticity may be modulated. As one indication of the evolutionary conservation of Kv1 channel functions, mutations of the Shaker potassium channel gene in Drosophila and the KCNA1 gene for its mammalian orthologue, Kv1.1, cause hyperexcitability near axon branch points and nerve terminals, thereby leading to uncontrolled movements and recapitulating the episodic ataxia-1 (EA1) symptoms in human patients.

Figure 1. Squid axons and vertebrate axons

Left, a schematic diagram of the squid giant axon emerging from the stellate ganglion. Middle, the squid stellate nerve containing the squid giant axon and other axons of small diameter. Right, the axon of a cortico-thalamic neuron in the macaque monkey. The left panel is from Giuditta et al. (2008) with permission of the American Physiological Society, while the middle panel and right panels are from Bucher & Goaillard (2011) with permission of Elsevier.

Figure 2. Kv1 channels in the axon collaterals and presynaptic boutons control action potential waveform

A, a pyramidal neuron filled with voltage-sensitive dye in layer 5 of the cortex. B, applying the Kv1 channel blocker α-dendrotoxin (DTX) slows the action potential recorded in the axon collaterals and presynaptic boutons in the boxed region in A, but causes much less broadening of the action potential recorded from the neuronal soma. The control recording is from a pixel adjacent to the bouton. C, the spike width in axon collaterals is sensitive to the Kv1 channel blockers α-DTX and 4-AP. D, α-DTX-sensitive Kv1 channels are crucial for somatic membrane potential changes to influence the spike width in axon collaterals and presynaptic boutons. E, application of α-DTX to the axon collaterals but not the neuronal soma abolishes the ability of subthreshold depolarization of neuronal soma to cause spike broadening in axon collaterals. From Foust et al. (2011) with permission of the Society for Neuroscience.

Figure 3. Loss of Kv1.1 function causes reentrant action potentials of mouse motor axons

Top, the experimental scheme for extracellular recording of the muscle compound action potential with a surface electrode in the phrenic nerve–diaphragm preparation of a P18 null mutant mice lacking Kv1.1. The action potentials are evoked either by stimulating the nerve (bottom right) or by directly stimulating the muscle (bottom left). In the absence of Kv1.1-containing channels, action potentials may ‘reflect’ from the nerve terminals and result in ‘backfiring’ along the motor axon. From Zhou et al. (1998) with permission of the Society for Neuroscience.

Figure 4. The Shaker mutant phenotypes observed at the larval neuromuscular junction

Left top, a Drosophila larval muscle innervated by motor axons stained with antibody against horseradish peroxidase (HRP) (Jan & Jan, 1982). Left bottom, Shaker mutant (Sh^KS133) larvae display much larger synaptic potentials at low (0.1 mm) external calcium concentration as compared to Canton-S (CS) wild-type larvae. From Jan et al. (1977) with permission of the Royal Society. Right, simultaneous recordings from the motor nerve (above) and muscle (below) in Shaker mutant (Sh^KS133) larvae, and in wild-type (CS) larvae treated with 6 mm 4-AP to block potassium channels. Stimulus artifacts are at the left end of the records. From Jan & Jan (1997).