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Hydrophobic interactions between the HA helix and S4‐S5 linker modulate apparent Ca2+ sensitivity of SK2 channels.

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Title: Hydrophobic interactions between the HA helix and S4‐S5 linker modulate apparent Ca2+ sensitivity of SK2 channels.
Authors: Nam, Young‐Woo (AUTHOR), Cui, Meng (AUTHOR), Orfali, Razan (AUTHOR), Viegas, Adam (AUTHOR), Nguyen, Misa (AUTHOR), Mohammed, Eman H. M. (AUTHOR), Zoghebi, Khalid A. (AUTHOR), Rahighi, Simin (AUTHOR), Parang, Keykavous (AUTHOR), Zhang, Miao (AUTHOR)
Source: Acta Physiologica. Jan2021, Vol. 231 Issue 1, p1-12. 12p. 1 Diagram, 6 Graphs.
Subjects: Hydrophobic interactions, Site-specific mutagenesis, Electrophysiology, Calmodulin
Abstract: Aim: Small‐conductance Ca2+‐activated potassium (SK) channels are activated exclusively by increases in intracellular Ca2+ that binds to calmodulin constitutively associated with the channel. Wild‐type SK2 channels are activated by Ca2+ with an EC50 value of ~0.3 μmol/L. Here, we investigate hydrophobic interactions between the HA helix and the S4‐S5 linker as a major determinant of channel apparent Ca2+ sensitivity. Methods: Site‐directed mutagenesis, electrophysiological recordings and molecular dynamic (MD) simulations were utilized. Results: Mutations that decrease hydrophobicity at the HA‐S4‐S5 interface lead to Ca2+ hyposensitivity of SK2 channels. Mutations that increase hydrophobicity result in hypersensitivity to Ca2+. The Ca2+ hypersensitivity of the V407F mutant relies on the interaction of the cognate phenylalanine with the S4‐S5 linker in the SK2 channel. Replacing the S4‐S5 linker of the SK2 channel with the S4‐S5 linker of the SK4 channel results in loss of the hypersensitivity caused by V407F. This difference between the S4‐S5 linkers of SK2 and SK4 channels can be partially attributed to I295 equivalent to a valine in the SK4 channel. A N293A mutation in the S4‐S5 linker also increases hydrophobicity at the HA‐S4‐S5 interface and elevates the channel apparent Ca2+ sensitivity. The double N293A/V407F mutations generate a highly Ca2+ sensitive channel, with an EC50 of 0.02 μmol/L. The MD simulations of this double‐mutant channel revealed a larger channel cytoplasmic gate. Conclusion: The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4‐S5 linker in the apparent Ca2+ sensitivity of SK2 channels. [ABSTRACT FROM AUTHOR]
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Label: Title
  Group: Ti
  Data: Hydrophobic interactions between the HA helix and S4‐S5 linker modulate apparent Ca<superscript>2+</superscript> sensitivity of SK2 channels.
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  Label: Authors
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  Data: <searchLink fieldCode="AR" term="%22Nam%2C+Young‐Woo%22">Nam, Young‐Woo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cui%2C+Meng%22">Cui, Meng</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Orfali%2C+Razan%22">Orfali, Razan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Viegas%2C+Adam%22">Viegas, Adam</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nguyen%2C+Misa%22">Nguyen, Misa</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mohammed%2C+Eman+H%2E+M%2E%22">Mohammed, Eman H. M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zoghebi%2C+Khalid+A%2E%22">Zoghebi, Khalid A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Rahighi%2C+Simin%22">Rahighi, Simin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Parang%2C+Keykavous%22">Parang, Keykavous</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhang%2C+Miao%22">Zhang, Miao</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Acta+Physiologica%22">Acta Physiologica</searchLink>. Jan2021, Vol. 231 Issue 1, p1-12. 12p. 1 Diagram, 6 Graphs.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Hydrophobic+interactions%22">Hydrophobic interactions</searchLink><br /><searchLink fieldCode="DE" term="%22Site-specific+mutagenesis%22">Site-specific mutagenesis</searchLink><br /><searchLink fieldCode="DE" term="%22Electrophysiology%22">Electrophysiology</searchLink><br /><searchLink fieldCode="DE" term="%22Calmodulin%22">Calmodulin</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Aim: Small‐conductance Ca2+‐activated potassium (SK) channels are activated exclusively by increases in intracellular Ca2+ that binds to calmodulin constitutively associated with the channel. Wild‐type SK2 channels are activated by Ca2+ with an EC50 value of ~0.3 μmol/L. Here, we investigate hydrophobic interactions between the HA helix and the S4‐S5 linker as a major determinant of channel apparent Ca2+ sensitivity. Methods: Site‐directed mutagenesis, electrophysiological recordings and molecular dynamic (MD) simulations were utilized. Results: Mutations that decrease hydrophobicity at the HA‐S4‐S5 interface lead to Ca2+ hyposensitivity of SK2 channels. Mutations that increase hydrophobicity result in hypersensitivity to Ca2+. The Ca2+ hypersensitivity of the V407F mutant relies on the interaction of the cognate phenylalanine with the S4‐S5 linker in the SK2 channel. Replacing the S4‐S5 linker of the SK2 channel with the S4‐S5 linker of the SK4 channel results in loss of the hypersensitivity caused by V407F. This difference between the S4‐S5 linkers of SK2 and SK4 channels can be partially attributed to I295 equivalent to a valine in the SK4 channel. A N293A mutation in the S4‐S5 linker also increases hydrophobicity at the HA‐S4‐S5 interface and elevates the channel apparent Ca2+ sensitivity. The double N293A/V407F mutations generate a highly Ca2+ sensitive channel, with an EC50 of 0.02 μmol/L. The MD simulations of this double‐mutant channel revealed a larger channel cytoplasmic gate. Conclusion: The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4‐S5 linker in the apparent Ca2+ sensitivity of SK2 channels. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=147580370
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        Value: 10.1111/apha.13552
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        Text: English
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        PageCount: 12
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      – SubjectFull: Hydrophobic interactions
        Type: general
      – SubjectFull: Site-specific mutagenesis
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      – SubjectFull: Electrophysiology
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      – SubjectFull: Calmodulin
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    Titles:
      – TitleFull: Hydrophobic interactions between the HA helix and S4‐S5 linker modulate apparent Ca2+ sensitivity of SK2 channels.
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              M: 01
              Text: Jan2021
              Type: published
              Y: 2021
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