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Molecular Pharmacology

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Research ArticleArticle

Structural Determinants of Kv7.5 Potassium Channels That Confer Changes in Phosphatidylinositol 4,5-Bisphosphate (PIP2) Affinity and Signaling Sensitivities in Smooth Muscle Cells

Lyubov I. Brueggemann, Leanne L. Cribbs and Kenneth L. Byron
Molecular Pharmacology March 2020, 97 (3) 145-158; DOI: https://doi.org/10.1124/mol.119.117192
Lyubov I. Brueggemann
Loyola University Chicago, Stritch School of Medicine, Departments of Molecular Pharmacology & Neuroscience (L.I.B., K.L.B.) and Cell and Molecular Physiology (L.L.C.), Maywood, Illinois
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Leanne L. Cribbs
Loyola University Chicago, Stritch School of Medicine, Departments of Molecular Pharmacology & Neuroscience (L.I.B., K.L.B.) and Cell and Molecular Physiology (L.L.C.), Maywood, Illinois
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Kenneth L. Byron
Loyola University Chicago, Stritch School of Medicine, Departments of Molecular Pharmacology & Neuroscience (L.I.B., K.L.B.) and Cell and Molecular Physiology (L.L.C.), Maywood, Illinois
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Abstract

Smooth muscle cells express Kv7.4 and Kv7.5 voltage-dependent potassium channels, which have each been implicated as regulators of smooth muscle contractility, though they display different sensitivities to signaling via cAMP/protein kinase A (PKA) and protein kinase C (PKC). We expressed chimeric channels composed of different components of the Kv7.4 and Kv7.5 α-subunits in vascular smooth muscle cells to determine which components are essential for enhancement or inhibition of channel activity. Forskolin, an activator of the cAMP/PKA pathway, increased wild-type Kv7.5 but not wild-type Kv7.4 current amplitude. Replacing the amino terminus of Kv7.4 with the amino terminus of Kv7.5 conferred partial responsiveness to forskolin. In contrast, swapping carboxy-terminal phosphatidylinositol 4,5-bisphosphate (PIP2) binding domains, or the entire C terminus, was without effect on the forskolin response, but the latter conferred responsiveness to arginine-vasopressin (an inhibitory PKC-dependent response). Serine-to-alanine mutation at position 53 of the Kv7.5 amino terminus abrogated its ability to confer forskolin sensitivity to Kv7.4. Forskolin treatment reduced the sensitivity of Kv7.5 channels to Ciona intestinalis voltage-sensing phosphatase (Ci-VSP)-induced PIP2 depletion, whereas activation of PKC with phorbol-12-myristate-13-acetate potentiated the Ci-VSP–induced decline in Kv7.5 current amplitude. Our findings suggest that PKA-dependent phosphorylation of serine 53 on the amino terminus of Kv7.5 increases its affinity for PIP2, whereas PKC-dependent phosphorylation of the Kv7.5 carboxy terminus is associated with a reduction in PIP2 affinity; these changes in PIP2 affinity have corresponding effects on channel activity. Resting affinities for PIP2 differ for Kv7.4 and Kv7.5 based on differential responsiveness to Ci-VSP activation and different rates of current rundown in ruptured patch recordings.

SIGNIFICANCE STATEMENT Kv7.4 and Kv7.5 channels are known signal transduction intermediates and drug targets for regulation of smooth muscle tone. The present studies identify distinct functional domains that confer differential sensitivities of Kv7.4 and Kv7.5 to stimulatory and inhibitory signaling and reveal structural features of the channel subunits that determine their biophysical properties. These findings may improve our understanding of the roles of these channels in smooth muscle physiology and disease, particularly in conditions where Kv7.4 and Kv7.5 are differentially expressed.

Footnotes

    • Received May 20, 2019.
    • Accepted December 16, 2019.
  • The project described was supported by award number I01BX007080 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development.

  • https://doi.org/10.1124/mol.119.117192.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 97 (3)
Molecular Pharmacology
Vol. 97, Issue 3
1 Mar 2020
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Research ArticleArticle

PKA and PKC Affect PIP2 Binding via N and C Termini of Kv7.5

Lyubov I. Brueggemann, Leanne L. Cribbs and Kenneth L. Byron
Molecular Pharmacology March 1, 2020, 97 (3) 145-158; DOI: https://doi.org/10.1124/mol.119.117192

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Research ArticleArticle

PKA and PKC Affect PIP2 Binding via N and C Termini of Kv7.5

Lyubov I. Brueggemann, Leanne L. Cribbs and Kenneth L. Byron
Molecular Pharmacology March 1, 2020, 97 (3) 145-158; DOI: https://doi.org/10.1124/mol.119.117192
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