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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.


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Kv7 channels structure, tissue distribution, human channelopathies, and disease target.
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Figure 1: Kv7 channels structure, tissue distribution, human channelopathies, and disease target.

Mentions: Among Kv channels, the Kv7 family encompasses five members (from Kv7.1 to Kv7.5), each showing a different tissue distribution and physiological role (Miceli et al., 2008a; Figure 1). Indeed, Kv7.1 is manly expressed in the heart, pancreas, thyroid gland, brain, gastrointestinal tract, portal vein, and the inner ear. In cardiac myocytes, in association with KCNE1, Kv7.1 underlies the slow component of IKs, a K+-selective current involved in the late phase of action potential repolarization. Kv7.2, Kv7.3, Kv7.4, and Kv7.5 show prevalently neuronal localization; homo- or hetero-tetrameric assembly of Kv7.2 and Kv7.3 subunits, with possible additional contribution from Kv7.4 and Kv7.5 subunits at specific neuronal sites, represents the molecular basis of the M-current (IKM), a slowly activating and deactivating K+ current highly regulated by Gq/11-coupled receptors (Delmas and Brown, 2005). IKM regulates membrane excitability in the sub-threshold range for action potential generation, acting as a brake for neuronal firing; indeed, reduction of this current is often sufficient to increase neuronal excitability. Kv7.4 subunits are mainly expressed in cochlear and vestibular organs of the inner hear, as well as in central auditory pathways (Kubisch et al., 1999); more recent work has revealed expression of Kv7.4 subunits also in skeletal muscle (Iannotti et al., 2010), as well as in visceral and vascular smooth muscle (Greenwood and Ohya, 2009). Kv7.5 expression, in addition to the brain, has been also detected in human adult skeletal muscle (Lerche et al., 2000; Schroeder et al., 2000), and, together with Kv7.1 and Kv7.4, in vascular smooth muscle cells (Yeung et al., 2007).


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)

Kv7 channels structure, tissue distribution, human channelopathies, and disease target.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Kv7 channels structure, tissue distribution, human channelopathies, and disease target.
Mentions: Among Kv channels, the Kv7 family encompasses five members (from Kv7.1 to Kv7.5), each showing a different tissue distribution and physiological role (Miceli et al., 2008a; Figure 1). Indeed, Kv7.1 is manly expressed in the heart, pancreas, thyroid gland, brain, gastrointestinal tract, portal vein, and the inner ear. In cardiac myocytes, in association with KCNE1, Kv7.1 underlies the slow component of IKs, a K+-selective current involved in the late phase of action potential repolarization. Kv7.2, Kv7.3, Kv7.4, and Kv7.5 show prevalently neuronal localization; homo- or hetero-tetrameric assembly of Kv7.2 and Kv7.3 subunits, with possible additional contribution from Kv7.4 and Kv7.5 subunits at specific neuronal sites, represents the molecular basis of the M-current (IKM), a slowly activating and deactivating K+ current highly regulated by Gq/11-coupled receptors (Delmas and Brown, 2005). IKM regulates membrane excitability in the sub-threshold range for action potential generation, acting as a brake for neuronal firing; indeed, reduction of this current is often sufficient to increase neuronal excitability. Kv7.4 subunits are mainly expressed in cochlear and vestibular organs of the inner hear, as well as in central auditory pathways (Kubisch et al., 1999); more recent work has revealed expression of Kv7.4 subunits also in skeletal muscle (Iannotti et al., 2010), as well as in visceral and vascular smooth muscle (Greenwood and Ohya, 2009). Kv7.5 expression, in addition to the brain, has been also detected in human adult skeletal muscle (Lerche et al., 2000; Schroeder et al., 2000), and, together with Kv7.1 and Kv7.4, in vascular smooth muscle cells (Yeung et al., 2007).

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