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Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies.

Tricarico D, Camerino DC - Front Pharmacol (2011)

Bottom Line: The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations.One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating.It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacobiology, Faculty of Pharmacy, University of Bari Italy.

ABSTRACT
The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations. Recent advances in thyrotoxic PP and hypokalemic PP (hypoPP) confirm the involvement of the muscle potassium channels in the pathogenesis of the diseases and their role as target of action for drugs of therapeutic interest. The novelty in the gating pore currents theory help to explain the disease symptoms, and open the possibility to more specifically target the disease. It is now known that the fiber depolarization in the hypoPP is due to an unbalance between the novel identified depolarizing gating pore currents (I(gp)) carried by protons or Na(+) ions flowing through aberrant alternative pathways of the mutant subunits and repolarizing inwardly rectifying potassium channel (Kir) currents which also includes the ATP-sensitive subtype. Abnormal activation of the I(gp) or deficiency in the Kir channels predispose to fiber depolarization. One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating. It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.

No MeSH data available.


Related in: MedlinePlus

Steady-state I–V relationships simulation in normal and hypoPP conditions, and molecular architecture of a Kir channel [modified from Kurachi and colleagues (Hibino et al., 2009) and Cannon (2010)]. The I–V relation for mammalian skeletal muscle was simulated by the combination of an inward rectifier K+ current, IKir, a delayed rectifier K+ current, IKDR, and a leakage current with a reversal potential of 0 mV, ILeak (A). In 4 mM [K+]o the resting potential of −91.3 mV is determined primarily from the balance of an inward ILeak and outward IKir. Addition of a gating pore current, Igp, to simulate hypoPP (dashed red line), shifts the I–V relation downward (dashed black line) but results in only a small depolarization of Vrest to −87.3 mV. The reduction of [K+]o to 2.5 mM shifts EK and IKir to more negative potentials, with a predicted hyperpolarization of Vrest to −101.6 mV in WT fibers. For hypoPP fibers, however, Vrest depolarizes to −65.3 mV (arrow) because the combination of inward currents (ILeak + Igp) exceeds the outward current from IKir. Modified from the original version of Cannon (2010) to evidence that in low external K+ ions the affinity of Mg2+ions, protons and other endogenous blockers of Kir channels for their inhibitory sites increase leading to the characteristic hump in the I–V relationship of the Kir current component. (B) A schematic representation of the structure of a generic Kir channel. The Kir channel is divided into transmembrane and cytoplasmic domains. The NH2 and COOH termini are cytosolic. Tetrameric assembly of Kir channels. The molecular architecture of a tetrameric Kir channel (protein database ID 2QKS: Kir3.1–KirBac3.1 chimera) is represented as a cartoon model reproduced and modified from Kurachi and colleagues (Hibino et al., 2009). The front subunit has been omitted for clarity. The organization of the tetramer of NH2 and COOH termini leads to an extended pore for ion permeation. The transmembrane domain comprises three helices: TM1, H5, and TM2. At the membrane–cytoplasm interface, there is also an amphiphilic slide helix which is a site for some AS mutations. The residue that is largely responsible for the interaction with polyamines and Mg2+ and thus inward rectification are located on TM2. In Kir6.2, the inhibitory binding sites for ATP are located in the cytoplasmic domains. TM1 contains the inhibitory binding sites for protons in the Kir1.1. Inhibitory sites for protons in other Kir channels as Kir2.3 are located also in the cytoplasmic regions affecting PiP2 binding. The opening of Kir channels requires PtdIns(4,5)P2 (PiP2). Those amino acid residues associated with the interaction with PiP2 are distributed on the surface of the cytoplasmic domain toward the plasma membrane. These are also the sites for most of the AS mutations in the Kir2.1. The cytoplasmic domain also contains most of the TPP mutations recently found in the Kir2.6.
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Figure 1: Steady-state I–V relationships simulation in normal and hypoPP conditions, and molecular architecture of a Kir channel [modified from Kurachi and colleagues (Hibino et al., 2009) and Cannon (2010)]. The I–V relation for mammalian skeletal muscle was simulated by the combination of an inward rectifier K+ current, IKir, a delayed rectifier K+ current, IKDR, and a leakage current with a reversal potential of 0 mV, ILeak (A). In 4 mM [K+]o the resting potential of −91.3 mV is determined primarily from the balance of an inward ILeak and outward IKir. Addition of a gating pore current, Igp, to simulate hypoPP (dashed red line), shifts the I–V relation downward (dashed black line) but results in only a small depolarization of Vrest to −87.3 mV. The reduction of [K+]o to 2.5 mM shifts EK and IKir to more negative potentials, with a predicted hyperpolarization of Vrest to −101.6 mV in WT fibers. For hypoPP fibers, however, Vrest depolarizes to −65.3 mV (arrow) because the combination of inward currents (ILeak + Igp) exceeds the outward current from IKir. Modified from the original version of Cannon (2010) to evidence that in low external K+ ions the affinity of Mg2+ions, protons and other endogenous blockers of Kir channels for their inhibitory sites increase leading to the characteristic hump in the I–V relationship of the Kir current component. (B) A schematic representation of the structure of a generic Kir channel. The Kir channel is divided into transmembrane and cytoplasmic domains. The NH2 and COOH termini are cytosolic. Tetrameric assembly of Kir channels. The molecular architecture of a tetrameric Kir channel (protein database ID 2QKS: Kir3.1–KirBac3.1 chimera) is represented as a cartoon model reproduced and modified from Kurachi and colleagues (Hibino et al., 2009). The front subunit has been omitted for clarity. The organization of the tetramer of NH2 and COOH termini leads to an extended pore for ion permeation. The transmembrane domain comprises three helices: TM1, H5, and TM2. At the membrane–cytoplasm interface, there is also an amphiphilic slide helix which is a site for some AS mutations. The residue that is largely responsible for the interaction with polyamines and Mg2+ and thus inward rectification are located on TM2. In Kir6.2, the inhibitory binding sites for ATP are located in the cytoplasmic domains. TM1 contains the inhibitory binding sites for protons in the Kir1.1. Inhibitory sites for protons in other Kir channels as Kir2.3 are located also in the cytoplasmic regions affecting PiP2 binding. The opening of Kir channels requires PtdIns(4,5)P2 (PiP2). Those amino acid residues associated with the interaction with PiP2 are distributed on the surface of the cytoplasmic domain toward the plasma membrane. These are also the sites for most of the AS mutations in the Kir2.1. The cytoplasmic domain also contains most of the TPP mutations recently found in the Kir2.6.

Mentions: Kir channels have a key role in the pathogenesis of hypoPP. Kir currents carried by the inwardly rectifier K+ channels which also include the ATP-sensitive type set the resting potentials close to the equilibrium potentials for K+ ions which is around −90 mV as calculated by Nernst equation in normal fibers. The inwardly rectifier K+ channels show a non-linear I–V curves with high permeability to K+ ions at negative membrane potentials which generates an elevated inward currents, and lower permeability at depolarized potentials generating much lower outward currents. This graphically generates an hump of the I–V curves which is an intrinsic properties of the Kir channel currents (Figure 1A). This is caused by the internal Mg2+ ions, polyamines and proton-block of the pore at millimolar concentrations which compete with K+ ions for the internal pore binding sites (Figures 1A,B). The blocking actions of these positively charged molecules and ions is voltage-dependent being more effective at depolarizing voltages. A potential gradient across the cell membrane removes this blockage during hyperpolarization but allow these cations to occlude the ion-conducting pore during depolarizations (Hibino et al., 2009). Rectification is important for setting the resting potential and aiding in repolarization of cells while shunting K+ currents during depolarizations allowing it. In normal fibers the lowering of external K+ ions from 4 to 2.5 mEq/L shift the I–V relationships of Kir currents and of total membrane currents to the left toward more negative values as predicted by the Nernst equation (Figure 1A; Cannon, 2010). However, the lowering of ext. K+ ions below 1.5 mEq/L reduces Kir outward currents shifting the I–V relationships of Kir currents and of total membrane currents to the right toward more positive values setting the resting potential at a new depolarized values. This is also called paradoxical membrane depolarization in low ext. K+ ions concentrations which is explained by the enhanced affinity of the Mg2+ ions and polyamines or protons for their inhibitory binding sites unmasked by the extremely low ext. K+ ions concentration (Figures 1 and 2; Hibino et al., 2009; Cannon, 2010). This is an intrinsic property of the Kir channel that play a key role in the pathogenesis of hypoPP and related diseases. One mechanism by which low intracellular pH inhibit channel opening is related with the reductions of the binding affinity of the channel to PtdIns(4,5)P2 interaction. This is observed at pH values of about 6.5 (Qu et al., 2000; Hibino et al., 2009). Pharmacological investigations support the involvement of the Kir channels in hypoPP. Barium toxicity produces a secondary form of hypoPP, and the Kir channel is blocked by Ba2+.


Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies.

Tricarico D, Camerino DC - Front Pharmacol (2011)

Steady-state I–V relationships simulation in normal and hypoPP conditions, and molecular architecture of a Kir channel [modified from Kurachi and colleagues (Hibino et al., 2009) and Cannon (2010)]. The I–V relation for mammalian skeletal muscle was simulated by the combination of an inward rectifier K+ current, IKir, a delayed rectifier K+ current, IKDR, and a leakage current with a reversal potential of 0 mV, ILeak (A). In 4 mM [K+]o the resting potential of −91.3 mV is determined primarily from the balance of an inward ILeak and outward IKir. Addition of a gating pore current, Igp, to simulate hypoPP (dashed red line), shifts the I–V relation downward (dashed black line) but results in only a small depolarization of Vrest to −87.3 mV. The reduction of [K+]o to 2.5 mM shifts EK and IKir to more negative potentials, with a predicted hyperpolarization of Vrest to −101.6 mV in WT fibers. For hypoPP fibers, however, Vrest depolarizes to −65.3 mV (arrow) because the combination of inward currents (ILeak + Igp) exceeds the outward current from IKir. Modified from the original version of Cannon (2010) to evidence that in low external K+ ions the affinity of Mg2+ions, protons and other endogenous blockers of Kir channels for their inhibitory sites increase leading to the characteristic hump in the I–V relationship of the Kir current component. (B) A schematic representation of the structure of a generic Kir channel. The Kir channel is divided into transmembrane and cytoplasmic domains. The NH2 and COOH termini are cytosolic. Tetrameric assembly of Kir channels. The molecular architecture of a tetrameric Kir channel (protein database ID 2QKS: Kir3.1–KirBac3.1 chimera) is represented as a cartoon model reproduced and modified from Kurachi and colleagues (Hibino et al., 2009). The front subunit has been omitted for clarity. The organization of the tetramer of NH2 and COOH termini leads to an extended pore for ion permeation. The transmembrane domain comprises three helices: TM1, H5, and TM2. At the membrane–cytoplasm interface, there is also an amphiphilic slide helix which is a site for some AS mutations. The residue that is largely responsible for the interaction with polyamines and Mg2+ and thus inward rectification are located on TM2. In Kir6.2, the inhibitory binding sites for ATP are located in the cytoplasmic domains. TM1 contains the inhibitory binding sites for protons in the Kir1.1. Inhibitory sites for protons in other Kir channels as Kir2.3 are located also in the cytoplasmic regions affecting PiP2 binding. The opening of Kir channels requires PtdIns(4,5)P2 (PiP2). Those amino acid residues associated with the interaction with PiP2 are distributed on the surface of the cytoplasmic domain toward the plasma membrane. These are also the sites for most of the AS mutations in the Kir2.1. The cytoplasmic domain also contains most of the TPP mutations recently found in the Kir2.6.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Steady-state I–V relationships simulation in normal and hypoPP conditions, and molecular architecture of a Kir channel [modified from Kurachi and colleagues (Hibino et al., 2009) and Cannon (2010)]. The I–V relation for mammalian skeletal muscle was simulated by the combination of an inward rectifier K+ current, IKir, a delayed rectifier K+ current, IKDR, and a leakage current with a reversal potential of 0 mV, ILeak (A). In 4 mM [K+]o the resting potential of −91.3 mV is determined primarily from the balance of an inward ILeak and outward IKir. Addition of a gating pore current, Igp, to simulate hypoPP (dashed red line), shifts the I–V relation downward (dashed black line) but results in only a small depolarization of Vrest to −87.3 mV. The reduction of [K+]o to 2.5 mM shifts EK and IKir to more negative potentials, with a predicted hyperpolarization of Vrest to −101.6 mV in WT fibers. For hypoPP fibers, however, Vrest depolarizes to −65.3 mV (arrow) because the combination of inward currents (ILeak + Igp) exceeds the outward current from IKir. Modified from the original version of Cannon (2010) to evidence that in low external K+ ions the affinity of Mg2+ions, protons and other endogenous blockers of Kir channels for their inhibitory sites increase leading to the characteristic hump in the I–V relationship of the Kir current component. (B) A schematic representation of the structure of a generic Kir channel. The Kir channel is divided into transmembrane and cytoplasmic domains. The NH2 and COOH termini are cytosolic. Tetrameric assembly of Kir channels. The molecular architecture of a tetrameric Kir channel (protein database ID 2QKS: Kir3.1–KirBac3.1 chimera) is represented as a cartoon model reproduced and modified from Kurachi and colleagues (Hibino et al., 2009). The front subunit has been omitted for clarity. The organization of the tetramer of NH2 and COOH termini leads to an extended pore for ion permeation. The transmembrane domain comprises three helices: TM1, H5, and TM2. At the membrane–cytoplasm interface, there is also an amphiphilic slide helix which is a site for some AS mutations. The residue that is largely responsible for the interaction with polyamines and Mg2+ and thus inward rectification are located on TM2. In Kir6.2, the inhibitory binding sites for ATP are located in the cytoplasmic domains. TM1 contains the inhibitory binding sites for protons in the Kir1.1. Inhibitory sites for protons in other Kir channels as Kir2.3 are located also in the cytoplasmic regions affecting PiP2 binding. The opening of Kir channels requires PtdIns(4,5)P2 (PiP2). Those amino acid residues associated with the interaction with PiP2 are distributed on the surface of the cytoplasmic domain toward the plasma membrane. These are also the sites for most of the AS mutations in the Kir2.1. The cytoplasmic domain also contains most of the TPP mutations recently found in the Kir2.6.
Mentions: Kir channels have a key role in the pathogenesis of hypoPP. Kir currents carried by the inwardly rectifier K+ channels which also include the ATP-sensitive type set the resting potentials close to the equilibrium potentials for K+ ions which is around −90 mV as calculated by Nernst equation in normal fibers. The inwardly rectifier K+ channels show a non-linear I–V curves with high permeability to K+ ions at negative membrane potentials which generates an elevated inward currents, and lower permeability at depolarized potentials generating much lower outward currents. This graphically generates an hump of the I–V curves which is an intrinsic properties of the Kir channel currents (Figure 1A). This is caused by the internal Mg2+ ions, polyamines and proton-block of the pore at millimolar concentrations which compete with K+ ions for the internal pore binding sites (Figures 1A,B). The blocking actions of these positively charged molecules and ions is voltage-dependent being more effective at depolarizing voltages. A potential gradient across the cell membrane removes this blockage during hyperpolarization but allow these cations to occlude the ion-conducting pore during depolarizations (Hibino et al., 2009). Rectification is important for setting the resting potential and aiding in repolarization of cells while shunting K+ currents during depolarizations allowing it. In normal fibers the lowering of external K+ ions from 4 to 2.5 mEq/L shift the I–V relationships of Kir currents and of total membrane currents to the left toward more negative values as predicted by the Nernst equation (Figure 1A; Cannon, 2010). However, the lowering of ext. K+ ions below 1.5 mEq/L reduces Kir outward currents shifting the I–V relationships of Kir currents and of total membrane currents to the right toward more positive values setting the resting potential at a new depolarized values. This is also called paradoxical membrane depolarization in low ext. K+ ions concentrations which is explained by the enhanced affinity of the Mg2+ ions and polyamines or protons for their inhibitory binding sites unmasked by the extremely low ext. K+ ions concentration (Figures 1 and 2; Hibino et al., 2009; Cannon, 2010). This is an intrinsic property of the Kir channel that play a key role in the pathogenesis of hypoPP and related diseases. One mechanism by which low intracellular pH inhibit channel opening is related with the reductions of the binding affinity of the channel to PtdIns(4,5)P2 interaction. This is observed at pH values of about 6.5 (Qu et al., 2000; Hibino et al., 2009). Pharmacological investigations support the involvement of the Kir channels in hypoPP. Barium toxicity produces a secondary form of hypoPP, and the Kir channel is blocked by Ba2+.

Bottom Line: The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations.One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating.It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacobiology, Faculty of Pharmacy, University of Bari Italy.

ABSTRACT
The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations. Recent advances in thyrotoxic PP and hypokalemic PP (hypoPP) confirm the involvement of the muscle potassium channels in the pathogenesis of the diseases and their role as target of action for drugs of therapeutic interest. The novelty in the gating pore currents theory help to explain the disease symptoms, and open the possibility to more specifically target the disease. It is now known that the fiber depolarization in the hypoPP is due to an unbalance between the novel identified depolarizing gating pore currents (I(gp)) carried by protons or Na(+) ions flowing through aberrant alternative pathways of the mutant subunits and repolarizing inwardly rectifying potassium channel (Kir) currents which also includes the ATP-sensitive subtype. Abnormal activation of the I(gp) or deficiency in the Kir channels predispose to fiber depolarization. One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating. It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.

No MeSH data available.


Related in: MedlinePlus