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Pathways modulating neural KCNQ/M (Kv7) potassium channels

Key Points

  • M channels are low-threshold voltage-gated K+ channels that regulate neuronal excitability. They are composed of members of the Kv7 (KCNQ) potassium channel family. Mutations in Kv7 genes cause neurological disorders such as epilepsy and deafness.

  • Kv7/M channels are inhibited by neurotransmitters that act on receptors coupled to the G protein Gq. Channels are activated by the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2). One effect of stimulating Gq-coupled receptors is the hydrolysis of PtdIns(4,5)P2. Therefore, one cause of channel closure is the consequent reduction in membrane PtdIns(4,5)P2 concentration.

  • Channel closure is also promoted by two products of PtdIns(4,5)P2 hydrolysis — inositol-1,4,5,-trisphosphate (Ins(1,4,5)P3), which raises intracellular Ca2+ and closes channels by activating channel-bound calmodulin; and diacylglycerol, which, in turn, activates protein kinase C (PKC) through a channel-attached protein, A-kinase anchoring protein 150 (AKAP150), and phosphorylates the channels.

  • We propose a unitary scheme for channel closure in which these PtdIns(4,5)P2 products modify the interaction of PtdIns(4,5)P2 with the channels.

  • Channel activity can also be increased by some drugs, by cysteine-alkylating agents and (for Kv7.2) by protein kinase A-mediated phosphorylation.

  • Modulation of M-channel activity through these various pathways, coupled with the differential sensitivities of different Kv7 subunits, provides mechanisms for fine-tuning neuronal activity in the short and long term.

Abstract

K+ channels play a crucial role in regulating the excitability of neurons. Many K+ channels are, in turn, regulated by neurotransmitters. One of the first neurotransmitter-regulated channels to be identified, some 25 years ago, was the M channel. This was categorized as such because its activity was inhibited through stimulation of muscarinic acetylcholine receptors. M channels are now known to be composed of subunits of the Kv7 (KCNQ) K+ channel family. However, until recently, the link between the receptors and the channels has remained elusive. Here, we summarize recent developments that have begun to clarify this link and discuss their implications for physiology and medicine.

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Figure 1: Some basic properties of the M current as originally observed in frog sympathetic neurons using twin microelectrode voltage-clamp recording.
Figure 2: Regulation of neuronal firing by the M current, as originally observed in a rat sympathetic neuron using single-microelectrode voltage-clamp recordings.
Figure 3: Structure of Kv7 channels: interaction sites on the carboxy-terminal tail of Kv7.2.
Figure 4: Schematic diagram of the phospholipase C-coupled pathway that links M1 muscarinic acetylcholine receptors to Kv7 channels.
Figure 5: Muscarinic inhibition of the M current is accompanied by hydrolysis of PtdIns(4,5)P2.
Figure 6: Relationship between PtdIns(4,5)P2 hydrolysis and M-current inhibition produced by the muscarinic agonist, oxotremorine-methiodide.
Figure 7: Signalling to Kv7/M channels.

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Acknowledgements

The authors' work has been supported by the UK Medical Research Council (D.A.B.), the European Union Framework Programs (D.A.B.), the Wellcome Trust (D.A.B. and P.D.) and the Centre National de la Recherche Scientifique (CNRS) (P.D.).

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DATABASES

Entrez Gene

AKAP

LHRH

NCS1

PLCβ

Src

FURTHER INFORMATION

Geocities web links

Potassium channels database

Potassium channel gene nomenclature

CNRS Cell Neurophysiology Laboratory

Faculty of 1000 author biography

Brown's homepage

Glossary

PHASICALLY FIRING NEURON

A neuron that responds with a transient discharge of action potentials when subjected to a long-lasting excitatory current.

TONICALLY FIRING NEURON

A neuron that responds with a sustained train of action potentials when subjected to a long-lasting excitatory current.

SHAKER CHANNEL

Prototypical inactivating K+ channel (Kv1) with six transmembrane segments.

CELL-ATTACHED MEMBRANE PATCH

A recording microelectrode is sealed onto a cell and allows the measurement of the current flowing through the ion channels embedded in the electrically-isolated membrane patch.

E-FOLD

Expresses the voltage-sensitivity of channel opening. The mathematical constant e (occasionally called Euler's number or Napier's constant) is the base of the natural logarithm function and its approximate value is 2.7182818284.

HOMER

Homer proteins belong to a wider family of PDZ domain-containing proteins and act as scaffolds, binding clusters of proteins and glutamate receptors at postsynaptic sites. PDZ domains are named after the proteins in which these sequence motifs were originally identified (postsynaptic density 95, discs large, zona occludens 1).

COINCIDENCE DETECTION

Kv7 channels can be seen as coincidence detection points of spatial and temporal signal integration. As such, an appropriately timed signal, otherwise ineffective, can alter channel gating by sensitizing the response to a convergent messenger, thereby playing a crucial part in adjusting neuronal output.

EVANESCENT SIGNALS

Signals that are short-lived and might result in transient, but not sustained, modification of channel gating. Such signals might be due to the fluctuating activities of kinases and phosphatases.

HEREDITARY LONG-QT SYNDROME

Familial disorder in which most affected family members have delayed ventricular repolarization manifest as QT prolongation. Affected individuals have an increased propensity to syncope, polymorphous ventricular tachycardia and sudden arrhythmic death.

ANDERSEN'S SYNDROME

A variant of Long-QT syndrome that is associated with clinical manifestations, including periodic paralysis, prolongation of the QT interval with ventricular arrhythmias, and characteristic physical features, including low-set ears, micrognathia and clinodactyly.

BARTTER'S SYNDROME

(Also known as K+ wasting). Involves a group of symptoms including enlargement of kidney cells associated with hypokalemic alkalosis and increased production of the hormone aldosterone. The condition is thought to be caused by a defect in the kidney's ability to reabsorb potassium.

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Delmas, P., Brown, D. Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci 6, 850–862 (2005). https://doi.org/10.1038/nrn1785

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