Subtype-selective Positive Modulation of K 2 Channels Depends on the HA/HB Helices

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2021 Aug 30

PMID 34458981

Citations 10

Authors

Young-Woo Nam

Meng Cui

Naglaa Salem El-Sayed

Razan Orfali

Misa Nguyen

Grace Yang

Mohammad Asikur Rahman

Judy Lee

Miao Zhang

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: In the activated state of small-conductance Ca -activated potassium (K 2) channels, calmodulin interacts with the HA/HB helices and the S4-S5 linker. CyPPA potentiates K 2.2a and K 2.3 channel activity but not the K 2.1 and K 3.1 subtypes.

Experimental Approach: Site-directed mutagenesis, patch-clamp recordings and in silico modelling were utilised to explore the structural determinants for the subtype-selective modulation of K 2 channels by CyPPA.

Key Results: Mutating residues in the HA (V420) and HB (K467) helices of K 2.2a channels to their equivalent residues in K 3.1 channels diminished the potency of CyPPA. CyPPA elicited prominent responses on mutant K 3.1 channels with an arginine residue in the HB helix substituted for its equivalent lysine residue in the K 2.2a channels (R355K). K 2.1 channels harbouring a three-amino-acid insertion upstream of the cognate R438 residues in the HB helix showed no response to CyPPA, whereas the deletion mutant (K 2.1_ΔA434/Q435/K436) became sensitive to CyPPA. In molecular dynamics simulations, CyPPA docked between calmodulin C-lobe and the HA/HB helices widens the cytoplasmic gate of K 2.2a channels.

Conclusion And Implications: Selectivity of CyPPA among K 2 and K 3.1 channel subtypes relies on the HA/HB helices.

Citing Articles

Atomistic mechanisms of the regulation of small-conductance Ca-activated K channel (SK2) by PIP2.

Woltz R, Zheng Y, Choi W, Ngo K, Trinh P, Ren L Proc Natl Acad Sci U S A. 2024; 121(39):e2318900121.

PMID: 39288178 PMC: 11441529. DOI: 10.1073/pnas.2318900121.

K2 and K3.1 Channels in the Airways: A New Therapeutic Target.

Orfali R, AlFaiz A, Rahman M, Lau L, Nam Y, Zhang M Biomedicines. 2023; 11(7).

PMID: 37509419 PMC: 10376499. DOI: 10.3390/biomedicines11071780.

K 2.2 (KCNN2): A physiologically and therapeutically important potassium channel.

Rahman M, Orfali R, Dave N, Lam E, Naguib N, Nam Y J Neurosci Res. 2023; 101(11):1699-1710.

PMID: 37466411 PMC: 10932612. DOI: 10.1002/jnr.25233.

Development and validation of an ultrahigh-performance liquid chromatography-tandem mass spectrometry method to investigate the plasma pharmacokinetics of a K 2.2/K 2.3 positive allosteric modulator in mice.

Rahman M, Chandrashekar D, Nam Y, Syed B, Salehi D, Montazeri Aliabadi H Rapid Commun Mass Spectrom. 2023; 37(15):e9537.

PMID: 37184249 PMC: 10330529. DOI: 10.1002/rcm.9537.

Loss-of-function K2.2 mutations abolish channel activity.

Nam Y, Rahman M, Yang G, Orfali R, Cui M, Zhang M Am J Physiol Cell Physiol. 2023; 324(3):C658-C664.

PMID: 36717104 PMC: 10069973. DOI: 10.1152/ajpcell.00584.2022.

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