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Neuromodulation of Na+ channels: An unexpected form of cellular platicity

Key Points

  • Voltage-gated Na+ channels consist of an α subunit in association with auxiliary β subunits. The α subunits consist of four homologous domains, each of which contains six transmembrane segments and a membrane re-entrant loop between S5 and S6. The S4 segments serve as the voltage sensors, the S5 and S6 segments and the re-entrant loop form the lining of the pore, and the short intracellular loop between domains III and IV forms the inactivation gate.

  • Voltage-gated Na+ channels are prime candidates for mediating cellular plasticity because they set the threshold for action potential generation. Analyses of Na+ channel regulation have revealed the molecular mechanism of neuromodulation of Na+ channels by protein phosphorylation via the cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) pathways.

  • Modulation of Na+ channels is implicated in the control of input–output relationships in several types of neuron including striatal, hippocampal, and cortical cells. Activation of several G-protein-coupled receptors that stimulate PKA and PKC can affect the functionality of native Na+ currents.

  • Na+-channel modulation is likely to be related to different aspects of nervous system physiology. For example, cocaine treatment and withdrawal can modulate Na+ channel function and hyeralgesia can lead to upregulation of Na+ channel activity. Furthermore, alteration of action potential generation in retinal ganglion neurons during contrast adaptation is likely to involve the modulation of Na+ channels.

Abstract

Voltage-gated Na+ channels set the threshold for action potential generation and are therefore good candidates to mediate forms of plasticity that affect the entire neuronal output. Although early studies led to the idea that Na+ channels were not subject to modulation, we now know that Na+ channel function is affected by phosphorylation. Furthermore, Na+ channel modulation is implicated in the control of input–output relationships in several types of neuron and seems to be involved in phenomena as varied as cocaine withdrawal, hyperalgesia and light adaptation. Here we review the available evidence for the regulation of Na+ channels by phosphorylation, its molecular mechanism, and the possible ways in which it affects neuronal function.

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Figure 1: Neurotransmitter pathways that modulate Na+ channels in hippocampal neurons.
Figure 2: Phosphorylation of Na+ channels and its functional effect in synaptosomes.
Figure 3: Contrasting effects of PKA modulation on Na+ currents in hippocampal and dorsal root ganglion neurons.
Figure 4: Changes in firing properties of neurons accompanying neuromodulation of Na+ channels.

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Authors and Affiliations

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DATABASE LINKS

Voltage-gated Na+ channels

PKA

PKC

calcineurin

M1

M3

M5

D1

D5

D2

D3

D4

FURTHER INFORMATION

The ion channel web page

Families of transport proteins

Glossary

CELLULAR PLASTICITY

A form of plasticity that modifies the entire output of a neuron.

SYNAPTOSOME

The presynaptic terminal isolated after subcellular fractionation. This structure retains the anatomical integrity of the terminal and can take up, store and release neurotransmitters.

PHORBOL ESTERS

Molecules capable of activating protein kinase C, probably by substituting for diacylglycerol. Phorbol esters can act as tumour promoters.

CELL-ATTACHED PATCH-CLAMP RECORDINGS

Recording configuration in which the patch of membrane at the tip of the recording electrode is not excised but remains attached to the whole cell.

STEADY-STATE INACTIVATION

The inactivation of a channel in response to prolonged changes in membrane voltage.

VERATRIDINE

Plant alkaloid that binds to Na+ channels and stabilizes them in the open state.

MEDIUM SPINY NEOSTRIATAL NEURONS

The main neuron population of the ventral and neuron dorsal striatum; these GABA projection neurons form the two main outputs of these structures, called the direct and indirect pathways.

CURRENT–VOLTAGE RELATIONSHIP

A plot of the changes in ionic current as a function of membrane voltage.

ANHEDONIA

Loss of interest or pleasure in almost all activities.

NUCLEUS BASALIS

Telencephalic nucleus. The main provider of cortical acetylcholine.

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Cantrell, A., Catterall, W. Neuromodulation of Na+ channels: An unexpected form of cellular platicity. Nat Rev Neurosci 2, 397–407 (2001). https://doi.org/10.1038/35077553

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