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The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants.

Miceli F, Soldovieri MV, Iannotti FA, Barrese V, Ambrosino P, Martire M, Cilio MR, Taglialatela M - Front Pharmacol (2011)

Bottom Line: In fact, genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns, and the pharmacological activation of K(v)7.2/3 channels can exert antiepileptic activity in humans.Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels.Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, IRCCS Bambino Gesù Children's Hospital Rome, Italy.

ABSTRACT
Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affecting heart rhythm (arrhythmias), neuronal excitability (epilepsy, pain), or skeletal muscle contraction (periodic paralysis). Moreover, gating changes appear as the main molecular mechanism by which several natural toxins from a variety of species affect ion channel function. In this work, we describe the pathophysiological and pharmacological relevance of the gating process in voltage-gated K(+) channels encoded by the K(v)7 gene family. After reviewing the current knowledge on the molecular mechanisms and on the structural models of voltage-dependent gating in VGICs, we describe the physiological relevance of these channels, with particular emphasis on those formed by K(v)7.2-K(v)7.5 subunits having a well-established role in controlling neuronal excitability in humans. In fact, genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns, and the pharmacological activation of K(v)7.2/3 channels can exert antiepileptic activity in humans. Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels. Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability.

No MeSH data available.


Related in: MedlinePlus

Sequence alignment of the relevant VSD regions of VGKCs (http://www.ebi.ac.uk/Tools/emboss/align/); residues are colored according to the following scheme: magenta, basic; blue, acid; red, non-polar; green, polar.
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Figure 2: Sequence alignment of the relevant VSD regions of VGKCs (http://www.ebi.ac.uk/Tools/emboss/align/); residues are colored according to the following scheme: magenta, basic; blue, acid; red, non-polar; green, polar.

Mentions: Sequence identity between Kv7.2 and the Kv1.2/2.1 chimera is 29%, and sequence similarity is 49%; these values are even higher when analysis is restricted to the VSD domain (see alignments in Figure 2). Based on this high degree of sequence homology, it seems plausible to predict an overall similar structural arrangement of the charged residues within the VSD between the two channels, although one important difference is the lack of the positively charged residue corresponding to R3 in all members of the Kv7 family, in which the R is replaced by a neutral glutamine (Q). Therefore, to provide insight into the possible structural consequences of the described mutations in the VSD causing BFNS, we built a homology model of the Kv7.2 subunit using the crystal coordinates of the Kv1.2/Kv2.1 chimera (Long et al., 2007). As previously discussed, the original crystal structure was obtained in the absence of transmembrane potential; thus, the model captures the VSD in the activated configuration (“up state”; Figure 3A). According to the previously discussed models, the VSD position is stabilized by ionized hydrogen bonds between the charged S4 Rs and the two clusters of negative charges. In particular, in the activated state, the positively charged residue at position 207 (corresponding to R4 in Figure 2) forms ionized hydrogen bonds with a negatively charged residue belonging to the external cluster (E130, E1 in Figure 2), whereas that at position 210 (corresponding to R5 in Figure 2) is predicted to interact with negative charges of the inner cluster (E140 in S2; D172 in S3 according to Kv7.2 numbering; respectively E2 and D1 in Figure 2). The two clusters are separated by the S2 phenylalanine gap (Phe 137 in Kv7.2).


The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants.

Miceli F, Soldovieri MV, Iannotti FA, Barrese V, Ambrosino P, Martire M, Cilio MR, Taglialatela M - Front Pharmacol (2011)

Sequence alignment of the relevant VSD regions of VGKCs (http://www.ebi.ac.uk/Tools/emboss/align/); residues are colored according to the following scheme: magenta, basic; blue, acid; red, non-polar; green, polar.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108560&req=5

Figure 2: Sequence alignment of the relevant VSD regions of VGKCs (http://www.ebi.ac.uk/Tools/emboss/align/); residues are colored according to the following scheme: magenta, basic; blue, acid; red, non-polar; green, polar.
Mentions: Sequence identity between Kv7.2 and the Kv1.2/2.1 chimera is 29%, and sequence similarity is 49%; these values are even higher when analysis is restricted to the VSD domain (see alignments in Figure 2). Based on this high degree of sequence homology, it seems plausible to predict an overall similar structural arrangement of the charged residues within the VSD between the two channels, although one important difference is the lack of the positively charged residue corresponding to R3 in all members of the Kv7 family, in which the R is replaced by a neutral glutamine (Q). Therefore, to provide insight into the possible structural consequences of the described mutations in the VSD causing BFNS, we built a homology model of the Kv7.2 subunit using the crystal coordinates of the Kv1.2/Kv2.1 chimera (Long et al., 2007). As previously discussed, the original crystal structure was obtained in the absence of transmembrane potential; thus, the model captures the VSD in the activated configuration (“up state”; Figure 3A). According to the previously discussed models, the VSD position is stabilized by ionized hydrogen bonds between the charged S4 Rs and the two clusters of negative charges. In particular, in the activated state, the positively charged residue at position 207 (corresponding to R4 in Figure 2) forms ionized hydrogen bonds with a negatively charged residue belonging to the external cluster (E130, E1 in Figure 2), whereas that at position 210 (corresponding to R5 in Figure 2) is predicted to interact with negative charges of the inner cluster (E140 in S2; D172 in S3 according to Kv7.2 numbering; respectively E2 and D1 in Figure 2). The two clusters are separated by the S2 phenylalanine gap (Phe 137 in Kv7.2).

Bottom Line: In fact, genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns, and the pharmacological activation of K(v)7.2/3 channels can exert antiepileptic activity in humans.Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels.Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, IRCCS Bambino Gesù Children's Hospital Rome, Italy.

ABSTRACT
Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affecting heart rhythm (arrhythmias), neuronal excitability (epilepsy, pain), or skeletal muscle contraction (periodic paralysis). Moreover, gating changes appear as the main molecular mechanism by which several natural toxins from a variety of species affect ion channel function. In this work, we describe the pathophysiological and pharmacological relevance of the gating process in voltage-gated K(+) channels encoded by the K(v)7 gene family. After reviewing the current knowledge on the molecular mechanisms and on the structural models of voltage-dependent gating in VGICs, we describe the physiological relevance of these channels, with particular emphasis on those formed by K(v)7.2-K(v)7.5 subunits having a well-established role in controlling neuronal excitability in humans. In fact, genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns, and the pharmacological activation of K(v)7.2/3 channels can exert antiepileptic activity in humans. Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels. Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability.

No MeSH data available.


Related in: MedlinePlus