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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

An homology model for drug binding to Kv7.2 channels. Top view of the overall structure of the channel formed by four identical Kv7.2 subunits (A), and enlarged view of a single Kv7.2 subunit (B) captured in the activated configuration. The residues involved in binding of retigabine (indicated in orange), zinc pyrithione (indicated in yellow), and NH29 (indicated in green) highlighted. The L275 residue in the pore, common to both retigabine and zinc pyrithione binding, is indicated in violet. The S1 region has been removed for clarity. The homology model of the Kv7.2 channel was generated as previously described (Miceli et al., 2008b).
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Figure 4: An homology model for drug binding to Kv7.2 channels. Top view of the overall structure of the channel formed by four identical Kv7.2 subunits (A), and enlarged view of a single Kv7.2 subunit (B) captured in the activated configuration. The residues involved in binding of retigabine (indicated in orange), zinc pyrithione (indicated in yellow), and NH29 (indicated in green) highlighted. The L275 residue in the pore, common to both retigabine and zinc pyrithione binding, is indicated in violet. The S1 region has been removed for clarity. The homology model of the Kv7.2 channel was generated as previously described (Miceli et al., 2008b).

Mentions: Mutagenesis and modeling experiments have suggested that, in channels formed by drug-sensitive Kv7 subunits, retigabine binds to a hydrophobic pocket located between the cytoplasmic parts of S5 and S6 in the open channel configuration. Within this cavity, a tryptophan residue in the intracellular end of the S5 helix (W236 in the Kv7.2 sequence) seems to play a crucial role (Schenzer et al., 2005; Wuttke et al., 2005; Figure 4A); replacement of W236 with a smaller and less hydrophobic leucine residue (naturally present at the corresponding position in retigabine-insensitive Kv7.1 subunits) largely prevents retigabine-induced IKM activation. Using a refined chimeric strategy, other residues crucial for retigabine-induced channel activation of Kv7.2 have been identified: in particular, L243 in S5, L275 in the pore, L299 and Gly301 (corresponding to the putative gating hinge in Long et al., 2005a,b) in the S6 segments of the neighboring subunit (according to Kv7.2 numbering; Lange et al., 2009; Figure 1; Table 1). Except for Leu275, all these amino acids are conserved among neural Kv7 subunits but are missing in cardiac Kv7.1 subunits. The conserved tryptophan residue within S5 is also a crucial structural element of the binding site for BMS-204352 and (S)-1 in Kv7.2–Kv7.5 channels (Bentzen et al., 2006; Blom et al., 2009), a result consistent with the lack of functional additivity observed when these compounds are applied together with retigabine.


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)

An homology model for drug binding to Kv7.2 channels. Top view of the overall structure of the channel formed by four identical Kv7.2 subunits (A), and enlarged view of a single Kv7.2 subunit (B) captured in the activated configuration. The residues involved in binding of retigabine (indicated in orange), zinc pyrithione (indicated in yellow), and NH29 (indicated in green) highlighted. The L275 residue in the pore, common to both retigabine and zinc pyrithione binding, is indicated in violet. The S1 region has been removed for clarity. The homology model of the Kv7.2 channel was generated as previously described (Miceli et al., 2008b).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: An homology model for drug binding to Kv7.2 channels. Top view of the overall structure of the channel formed by four identical Kv7.2 subunits (A), and enlarged view of a single Kv7.2 subunit (B) captured in the activated configuration. The residues involved in binding of retigabine (indicated in orange), zinc pyrithione (indicated in yellow), and NH29 (indicated in green) highlighted. The L275 residue in the pore, common to both retigabine and zinc pyrithione binding, is indicated in violet. The S1 region has been removed for clarity. The homology model of the Kv7.2 channel was generated as previously described (Miceli et al., 2008b).
Mentions: Mutagenesis and modeling experiments have suggested that, in channels formed by drug-sensitive Kv7 subunits, retigabine binds to a hydrophobic pocket located between the cytoplasmic parts of S5 and S6 in the open channel configuration. Within this cavity, a tryptophan residue in the intracellular end of the S5 helix (W236 in the Kv7.2 sequence) seems to play a crucial role (Schenzer et al., 2005; Wuttke et al., 2005; Figure 4A); replacement of W236 with a smaller and less hydrophobic leucine residue (naturally present at the corresponding position in retigabine-insensitive Kv7.1 subunits) largely prevents retigabine-induced IKM activation. Using a refined chimeric strategy, other residues crucial for retigabine-induced channel activation of Kv7.2 have been identified: in particular, L243 in S5, L275 in the pore, L299 and Gly301 (corresponding to the putative gating hinge in Long et al., 2005a,b) in the S6 segments of the neighboring subunit (according to Kv7.2 numbering; Lange et al., 2009; Figure 1; Table 1). Except for Leu275, all these amino acids are conserved among neural Kv7 subunits but are missing in cardiac Kv7.1 subunits. The conserved tryptophan residue within S5 is also a crucial structural element of the binding site for BMS-204352 and (S)-1 in Kv7.2–Kv7.5 channels (Bentzen et al., 2006; Blom et al., 2009), a result consistent with the lack of functional additivity observed when these compounds are applied together with retigabine.

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