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  • Review Article
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Non-conducting functions of voltage-gated ion channels

Nature Reviews Neuroscience volume 7, pages 761–771 (2006)Cite this article

Key Points

  • In addition to their well-understood role in determining the electrical activity of neurons, there exists evidence linking the expression of specific channels to cell proliferation. Such evidence has been obtained for several voltage-dependent K+ and Na+ channels and for several members of the non-selective TRP family of channels.

  • The pore-forming α-subunit of ether-à-go-go (EAG) channels has been found to activate Ca2+/calmodulin-dependent protein kinase II (CaMKII). The conformation of this channel has also been found to be coupled to the mitogen-activated protein kinase (MAPK) signalling pathway through a mechanism that is independent of ion flux through the channel.

  • Overexpression of the voltage-dependent Shal K+ channel in lobster neurons produces a compensatory increase in HCN channel activity. The increase in non-selective cation current opposes the increase in Shal K+ current, allowing the neurons to maintain their physiological pattern of bursting.

  • The β-subunits of K+ channels have been found to have various intrinsic enzyme activities. These include protein kinase and aldo reductase functions, and transcription factor activity.

  • The β-subunits of voltage-dependent Na+ channels have large extracellular domains that mediate cell–cell adhesion and repulsion, or promote neuriteoutgrowth through interactions with other cell adhesion molecules or through interactions with β-subunits on other cells.

  • Neuronal voltage-dependent Ca2+ channels can be linked directly to the synaptic release machinery at presynaptic endings. The conformation of these channels might also directly modulate the exocytosis of synaptic vesicles.

  • Transient activation of neuronal voltage-dependent Ca2+ channels activates the MAPK/ERK signalling pathway, resulting in activation of the transcription factor CREB. The activation of this pathway requires a local interaction between Ca2+ entering the channel and calmodulin, which is tightly bound to the C-terminus of the channel protein.

  • Non-selective cation channels of the TRP family have a variety of cellular actions that could be a result of their ability to interact with cytoplasmic elements. The α-subunits of some TRPM subfamily channels have intrinsic protein kinase activity, and subunits of the TRPP subfamily can regulate cell proliferation and morphogenesis by mechanisms partially independent of ion conduction.

Abstract

Various studies, mostly in the past 5 years, have demonstrated that, in addition to their well-described function in regulating electrical excitability, voltage-dependent ion channels participate in intracellular signalling pathways. Channels can directly activate enzymes linked to cellular signalling pathways, serve as cell adhesion molecules or components of the cytoskeleton, and their activity can alter the expression of specific genes. Here, I review these findings and discuss the extent to which the molecular mechanisms of such signalling are understood.

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Figure 1: Actions of K+ channels that do not require the conduction of K+ ions.
Figure 2: Enzyme activities that are intrinsic to the α- and β-subunits of ion channels.
Figure 3: Na+ Channel β-subunits function in cell adhesion.

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Acknowledgements

I am grateful to G. Wilson for very helpful discussions. The author's work is supported by grants from the National Institutes of Health (NIH).

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  1. Departments of Pharmacology and Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Leonard K. Kaczmarek

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Glossary

Integrins

Receptors on cells that interact with extracellular matrix proteins or other cell surface molecules, and that regulate important functions such as growth and survival.

A-type potassium currents

Also known as transient outward currents. A K+ current that undergoes inactivation over tens to hundreds of milliseconds during a maintained depolarization. Many A-type currents undergo steady-state inactivation at the resting potential. However, when the neuron fires repeatedly, this steady-state inactivation is removed during the afterhyperpolarization that follows each action potential. The subsequent transient activation of the A-type channel delays the next action potential and slows the firing rate.

Stomatogastric ganglion

A small and well-studied neural network in the stomach of crustaceans. This group of neurons generates a rhythmic input to stomach muscles, causing the physical disruption of food and its movement through the stomach.

Aldo reductases

Broad specificity enzymes that catalyse the conversion of aldehydes to alcohols while simultaneously oxidizing NADPH to NADP+.

Presenilins

The transmembrane proteins presenilin 1 and 2 are components of a large, multisubunit aspartyl protease complex termed γ-secretase. The presenilin/γ-secretase complex is required for the intramembranous cleavage of a variety of membrane proteins.

SNARE proteins

A family of membrane-tethered coiled–coil proteins that are required for membrane fusion in exocytosis (such as during neurotransmitter release) and other membrane transport events. When trans-SNARE complexes are formed between vesicle SNAREs and target-membrane SNAREs, they pull the two membranes together, presumably causing them to fuse.

Alternative splicing

A post-transcriptional process through which a pre-mRNA molecule, containing several introns and exons, can lead to different functional mRNA molecules, and consequently proteins, that originate from a single gene.

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Kaczmarek, L. Non-conducting functions of voltage-gated ion channels. Nat Rev Neurosci 7, 761–771 (2006). https://doi.org/10.1038/nrn1988

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