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Immunomodulation of voltage-dependent K+ channels in macrophages: molecular and biophysical consequences.

Villalonga N, David M, Bielanska J, Vicente R, Comes N, Valenzuela C, Felipe A - J. Gen. Physiol. (2010)

Bottom Line: An increase in K(+) current amplitude in lipopolysaccharide-activated macrophages is characterized by a faster C-type inactivation, a greater percentage of cumulative inactivation, and a more effective margatoxin (MgTx) inhibition than control cells.In contrast, dexamethasone decreased the C-type inactivation, the cumulative inactivation, and the sensitivity to MgTx concomitantly with a decrease in K(v)1.3 expression.Our results demonstrate that the immunomodulation of macrophages triggers molecular and biophysical consequences in K(v)1.3/K(v)1.5 hybrid channels by altering the subunit stoichiometry.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biología Molecular, Institut de Biomedicina, Universitat de Barcelona, E-08028 Barcelona, Spain.

ABSTRACT
Voltage-dependent potassium (K(v)) channels play a pivotal role in the modulation of macrophage physiology. Macrophages are professional antigen-presenting cells and produce inflammatory and immunoactive substances that modulate the immune response. Blockage of K(v) channels by specific antagonists decreases macrophage cytokine production and inhibits proliferation. Numerous pharmacological agents exert their effects on specific target cells by modifying the activity of their plasma membrane ion channels. Investigation of the mechanisms involved in the regulation of potassium ion conduction is, therefore, essential to the understanding of potassium channel functions in the immune response to infection and inflammation. Here, we demonstrate that the biophysical properties of voltage-dependent K(+) currents are modified upon activation or immunosuppression in macrophages. This regulation is in accordance with changes in the molecular characteristics of the heterotetrameric K(v)1.3/K(v)1.5 channels, which generate the main K(v) in macrophages. An increase in K(+) current amplitude in lipopolysaccharide-activated macrophages is characterized by a faster C-type inactivation, a greater percentage of cumulative inactivation, and a more effective margatoxin (MgTx) inhibition than control cells. These biophysical parameters are related to an increase in K(v)1.3 subunits in the K(v)1.3/K(v)1.5 hybrid channel. In contrast, dexamethasone decreased the C-type inactivation, the cumulative inactivation, and the sensitivity to MgTx concomitantly with a decrease in K(v)1.3 expression. Neither of these treatments apparently altered the expression of K(v)1.5. Our results demonstrate that the immunomodulation of macrophages triggers molecular and biophysical consequences in K(v)1.3/K(v)1.5 hybrid channels by altering the subunit stoichiometry.

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Diagram of major heterotetrameric structures in Raw macrophages upon immunomodulation. Raw cells express Kv1.3 and Kv1.5. Because MgTx abolished Kv currents, Kv1.5 does not form homomeric complexes. However, molecular, pharmacological, and biophysical data indicate that Raw cells express more Kv1.5 than Kv1.3. LPS-induced macrophages increased the number of Kv1.3 subunits at the complex. However, the immunosuppressant DEX decreases Kv1.3, which generates Kv1.5-predominant heteromeric channels. Different Kv1.3/Kv1.5 molecular ratios are responsible for the biophysical properties that lead to functional consequences during activation and immunosuppression. White circles, Kv1.3; black circles, Kv1.5.
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fig9: Diagram of major heterotetrameric structures in Raw macrophages upon immunomodulation. Raw cells express Kv1.3 and Kv1.5. Because MgTx abolished Kv currents, Kv1.5 does not form homomeric complexes. However, molecular, pharmacological, and biophysical data indicate that Raw cells express more Kv1.5 than Kv1.3. LPS-induced macrophages increased the number of Kv1.3 subunits at the complex. However, the immunosuppressant DEX decreases Kv1.3, which generates Kv1.5-predominant heteromeric channels. Different Kv1.3/Kv1.5 molecular ratios are responsible for the biophysical properties that lead to functional consequences during activation and immunosuppression. White circles, Kv1.3; black circles, Kv1.5.

Mentions: Fig. 9 illustrates several possible heterotetrameric structures in macrophages upon activation and immunosuppression. Macrophages express Kv1.3 and Kv1.5. Because MgTx abolished Kv currents regardless of the immunomodulatory agent, we can conclude that, similar to human dendritic cells (Zsiros et al., 2009), Kv1.5 apparently does not form homomeric complexes. However, the presence of structures solely formed by Kv1.3 cannot be ruled out. We have previously shown that, based on biophysical, molecular, and pharmacological studies, the major Kv channel in Raw macrophages is generated by structures where the predominant subunit is Kv1.5 (Villalonga et al., 2007). Different Kv1.3/Kv1.5 ratios are responsible for the biophysical consequences, fine-tuning the immune response after GC exposure or during an insult.


Immunomodulation of voltage-dependent K+ channels in macrophages: molecular and biophysical consequences.

Villalonga N, David M, Bielanska J, Vicente R, Comes N, Valenzuela C, Felipe A - J. Gen. Physiol. (2010)

Diagram of major heterotetrameric structures in Raw macrophages upon immunomodulation. Raw cells express Kv1.3 and Kv1.5. Because MgTx abolished Kv currents, Kv1.5 does not form homomeric complexes. However, molecular, pharmacological, and biophysical data indicate that Raw cells express more Kv1.5 than Kv1.3. LPS-induced macrophages increased the number of Kv1.3 subunits at the complex. However, the immunosuppressant DEX decreases Kv1.3, which generates Kv1.5-predominant heteromeric channels. Different Kv1.3/Kv1.5 molecular ratios are responsible for the biophysical properties that lead to functional consequences during activation and immunosuppression. White circles, Kv1.3; black circles, Kv1.5.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2812499&req=5

fig9: Diagram of major heterotetrameric structures in Raw macrophages upon immunomodulation. Raw cells express Kv1.3 and Kv1.5. Because MgTx abolished Kv currents, Kv1.5 does not form homomeric complexes. However, molecular, pharmacological, and biophysical data indicate that Raw cells express more Kv1.5 than Kv1.3. LPS-induced macrophages increased the number of Kv1.3 subunits at the complex. However, the immunosuppressant DEX decreases Kv1.3, which generates Kv1.5-predominant heteromeric channels. Different Kv1.3/Kv1.5 molecular ratios are responsible for the biophysical properties that lead to functional consequences during activation and immunosuppression. White circles, Kv1.3; black circles, Kv1.5.
Mentions: Fig. 9 illustrates several possible heterotetrameric structures in macrophages upon activation and immunosuppression. Macrophages express Kv1.3 and Kv1.5. Because MgTx abolished Kv currents regardless of the immunomodulatory agent, we can conclude that, similar to human dendritic cells (Zsiros et al., 2009), Kv1.5 apparently does not form homomeric complexes. However, the presence of structures solely formed by Kv1.3 cannot be ruled out. We have previously shown that, based on biophysical, molecular, and pharmacological studies, the major Kv channel in Raw macrophages is generated by structures where the predominant subunit is Kv1.5 (Villalonga et al., 2007). Different Kv1.3/Kv1.5 ratios are responsible for the biophysical consequences, fine-tuning the immune response after GC exposure or during an insult.

Bottom Line: An increase in K(+) current amplitude in lipopolysaccharide-activated macrophages is characterized by a faster C-type inactivation, a greater percentage of cumulative inactivation, and a more effective margatoxin (MgTx) inhibition than control cells.In contrast, dexamethasone decreased the C-type inactivation, the cumulative inactivation, and the sensitivity to MgTx concomitantly with a decrease in K(v)1.3 expression.Our results demonstrate that the immunomodulation of macrophages triggers molecular and biophysical consequences in K(v)1.3/K(v)1.5 hybrid channels by altering the subunit stoichiometry.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biología Molecular, Institut de Biomedicina, Universitat de Barcelona, E-08028 Barcelona, Spain.

ABSTRACT
Voltage-dependent potassium (K(v)) channels play a pivotal role in the modulation of macrophage physiology. Macrophages are professional antigen-presenting cells and produce inflammatory and immunoactive substances that modulate the immune response. Blockage of K(v) channels by specific antagonists decreases macrophage cytokine production and inhibits proliferation. Numerous pharmacological agents exert their effects on specific target cells by modifying the activity of their plasma membrane ion channels. Investigation of the mechanisms involved in the regulation of potassium ion conduction is, therefore, essential to the understanding of potassium channel functions in the immune response to infection and inflammation. Here, we demonstrate that the biophysical properties of voltage-dependent K(+) currents are modified upon activation or immunosuppression in macrophages. This regulation is in accordance with changes in the molecular characteristics of the heterotetrameric K(v)1.3/K(v)1.5 channels, which generate the main K(v) in macrophages. An increase in K(+) current amplitude in lipopolysaccharide-activated macrophages is characterized by a faster C-type inactivation, a greater percentage of cumulative inactivation, and a more effective margatoxin (MgTx) inhibition than control cells. These biophysical parameters are related to an increase in K(v)1.3 subunits in the K(v)1.3/K(v)1.5 hybrid channel. In contrast, dexamethasone decreased the C-type inactivation, the cumulative inactivation, and the sensitivity to MgTx concomitantly with a decrease in K(v)1.3 expression. Neither of these treatments apparently altered the expression of K(v)1.5. Our results demonstrate that the immunomodulation of macrophages triggers molecular and biophysical consequences in K(v)1.3/K(v)1.5 hybrid channels by altering the subunit stoichiometry.

Show MeSH
Related in: MedlinePlus