Trends in Neurosciences
Volume 23, Issue 9, 1 September 2000, Pages 393-398
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Perspective
KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy

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Abstract

In 1998, the discovery of two novel genes KCNQ2 and KCNQ3, mutated in a rare inherited form of epilepsy known as benign familial neonatal convulsions, for the first time enabled insight into the molecular etiology of a human idiopathic generalized epilepsy syndrome. These disease genes encode subunits of neuronal M-type K+ channels, key regulators of brain excitability. Analogies between benign familial neonatal convulsions and other channelopathies of skeletal and cardiac muscle, including periodic paralysis, myotonia and the long QT syndrome, provide clues about the nature of epilepsy-susceptibility genes and about the fundamental basis of epilepsy as an episodic disorder. It now appears that the KCNQ2/KCNQ3 K+ channels that are mutated in benign familial neonatal convulsions represent an important new target for anti-epileptic drugs. In the future, the identification of ion channel defects as predisposing factors in the common epilepsies could herald a new era of genotype-specific therapies.

Section snippets

BFNC is caused by a partial reduction in the KCNQ2/KCNQ3 K+ current

KCNQ2 and KCNQ3 encode proteins with sequence homology to members of the six-transmembrane domain K+ channel gene superfamily (Fig. 1, Fig. 2). Characteristic of K+ channel subunit proteins, KCNQ2 and KCNQ3 contain a highly conserved region rich in positively charged arginine residues in the fourth transmembrane domain (S4 helix) that is believed to serve as a voltage sensor, and a pore domain (P-loop) bearing the consensus sequence Thr-x-x-Thr-x-Gly-Tyr-Gly (Fig. 3). Although KCNQ2 and KCNQ3

M-current and seizures

In 1980, David Brown and Paul Adams described the existence of a low-threshold, noninactivating voltage-dependent K+ current in neurons, referred to as the M-current, which plays a dominant role in regulating excitability because of its unique activity in the voltage range of action-potential initiation10, 11. The M-current slowly activates when an excitatory stimulus depolarizes the neuron toward spike threshold, repolarizing the membrane back toward resting potential and suppressing firing.

KCNQ2 and KCNQ3 as epilepsy-susceptibility genes

BFNC is a rare disorder, having an incidence in the general population of about 1 in 100 000. However, idiopathic epilepsies with simple inheritance like BFNC are intensely scrutinized because of the potential they hold for understanding the pathogenesis of the sporadic epilepsies that account for the majority of cases seen in clinical practice. BFNC is characterized by frequent, brief, unprovoked, generalized or multifocal tonic-clonic seizures usually starting around the third day after birth

KCNQ gene subfamily

The KCNQ2 and KCNQ3 genes affected in BFNC exhibit a high degree of homology with the K+ channel gene KvLQT1 (now referred to as KCNQ1), which is expressed in the heart and is altered in the most common form of the long QT (Romano–Ward) syndrome, a cardiac disorder associated with the often fatal torsade de pointes ventricular arrhythmia20. BFNC and the long QT syndrome are similar in that affected individuals have normal functioning punctuated by attacks of dysfunction. Until recently, the

Epilepsy susceptibility associated with other K+ channel defects

An additional situation where a K+ channel mutation is known to confer epilepsy susceptibility is in episodic ataxia type 1 (EA1), a rare autosomal dominant disorder characterized by brief episodes of ataxia triggered by physical or emotional stress and persistent myokymia (rippling contractions of muscle). EA1 is associated with a defect in the KCNA1 (Kv1.1) voltage-dependent K+ channel gene27, 28. Mutations in KCNA1 associated with EA1 result in either defective channel-gating or a

Lessons from the channelopathies of skeletal and cardiac muscle

A particularly vexing problem in epileptology has been to explain why seizures occur episodically in susceptible individuals who might have entirely normal brain function between attacks. The recognition that at least some forms of idiopathic epilepsy are channelopathies, suggesting that a look at other members of this class of disorders might be instructive33 (Table 2). In many of the channelopathies, particularly those affecting skeletal and cardiac muscle, dysfunction occurs in a paroxysmal

Hidden suceptibility in channelopathies

The concept of hidden seizure susceptibility of adults carrying the BFNC and EA1 genes has a parallel in the long QT syndrome because some long QT syndrome mutations can be clinically silent until symptoms are elicited by a provocative stimulus34, 35. For example, some mutations in the 3′ portion of HERG, the gene encoding the principal α-subunit of the cardiac rapid delayed rectifier IKr, have been found to be largely benign unless carriers are exposed to hypokalemia or if they carry an

Molecular pathogenesis of epilepsy

By analogy with the channelopathies of muscle, some forms of epilepsy might be caused by alterations in ion channels that lead to a reduced repolarization reserve or that increase or prolong excitation. For example, in BFNC there is a defect in repolarization reserve mediated by M-currents. (It is speculated that the resolution of BFNC with brain maturation is as a result of the increase in repolarization reserve accompanying the expression of a greater number or diversity of K+ channels.) In

Therapeutic approaches in the channelopathies

Understanding the molecular pathophysiology of the channelopathies has provided a basis for defining the mechanisms of action of the empirical therapies of the pre-genetic era and for the development of new highly targeted, genotype-specific treatment approaches. For example, mexiletine and other Na+ channel blockers are often used in the treatment of myotonic syndromes43. However, mexiletine is more effective in paramyotonia congenita and K+ aggrevated myotonia than in hyperkalemic periodic

Openers of KCNQ2/KCNQ3 K+ channels are anticonvulsant

Because of the key role of K+ channels in dampening neuronal excitability, it has been suggested that K+ channel openers could have anticonvulsant activity12. In fact, there is evidence that openers of ATP-sensitive K+ channels have anticonvulsant properties in some in vitro and in vivo models49. However, because of their ubiquity in non-neural tissues, including muscle and glands, openers of ATP-sensitive K+ channels (and many other ubiquitous K+ channels) are expected to have unacceptable

Conclusion

With the exception of migraine, the epilepsies are the most common episodic neurological disorders. However, until recently, an understanding of the cellular and molecular bases of human seizure susceptibility remained elusive. As episodic disorders, there is a striking similarity between the epilepsies and various channelopathies of skeletal and cardiac muscle, and it now appears that some forms of idiopathic epilepsy are the result of subtle defects in channel function. The discovery of ion

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