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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

Proposed cascade of the pathogenic events in the hypokalemic periodic paralysis. The unbalance between the depolarizing and repolarizing current components is due to an abnormal activation of depolarizing gating pore currents (Igp) with increased influx of protons or Na+ ions through mutants and to the abnormal reduction of the repolarizing Kir currents carried by various subtypes of Kir channels. The insulin/glucose administration induces activation of the 3Na+/2K+-ATPase but failed to activate KATP channels causing a marked hypokalemia. The hypokalemia reduces the gene expression/activity of the Kir6.2 and SUR2A subunits. All these factors contribute to the fiber depolarization setting the resting potentials to a new value of −60 mV (Vm). The depolarization of the fibers inactivates the voltage-dependent Na+ and Ca2+ channels with paralysis.
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Figure 2: Proposed cascade of the pathogenic events in the hypokalemic periodic paralysis. The unbalance between the depolarizing and repolarizing current components is due to an abnormal activation of depolarizing gating pore currents (Igp) with increased influx of protons or Na+ ions through mutants and to the abnormal reduction of the repolarizing Kir currents carried by various subtypes of Kir channels. The insulin/glucose administration induces activation of the 3Na+/2K+-ATPase but failed to activate KATP channels causing a marked hypokalemia. The hypokalemia reduces the gene expression/activity of the Kir6.2 and SUR2A subunits. All these factors contribute to the fiber depolarization setting the resting potentials to a new value of −60 mV (Vm). The depolarization of the fibers inactivates the voltage-dependent Na+ and Ca2+ channels with paralysis.

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)

Proposed cascade of the pathogenic events in the hypokalemic periodic paralysis. The unbalance between the depolarizing and repolarizing current components is due to an abnormal activation of depolarizing gating pore currents (Igp) with increased influx of protons or Na+ ions through mutants and to the abnormal reduction of the repolarizing Kir currents carried by various subtypes of Kir channels. The insulin/glucose administration induces activation of the 3Na+/2K+-ATPase but failed to activate KATP channels causing a marked hypokalemia. The hypokalemia reduces the gene expression/activity of the Kir6.2 and SUR2A subunits. All these factors contribute to the fiber depolarization setting the resting potentials to a new value of −60 mV (Vm). The depolarization of the fibers inactivates the voltage-dependent Na+ and Ca2+ channels with paralysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108473&req=5

Figure 2: Proposed cascade of the pathogenic events in the hypokalemic periodic paralysis. The unbalance between the depolarizing and repolarizing current components is due to an abnormal activation of depolarizing gating pore currents (Igp) with increased influx of protons or Na+ ions through mutants and to the abnormal reduction of the repolarizing Kir currents carried by various subtypes of Kir channels. The insulin/glucose administration induces activation of the 3Na+/2K+-ATPase but failed to activate KATP channels causing a marked hypokalemia. The hypokalemia reduces the gene expression/activity of the Kir6.2 and SUR2A subunits. All these factors contribute to the fiber depolarization setting the resting potentials to a new value of −60 mV (Vm). The depolarization of the fibers inactivates the voltage-dependent Na+ and Ca2+ channels with paralysis.
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