Document Type
Article
Publication Date
8-30-2021
Abstract
Background and Purpose
In the activated state of small-conductance Ca2+-activated potassium (KCa 2) channels, calmodulin interacts with the HA/HB helices and the S4-S5 linker. CyPPA potentiates KCa 2.2a and KCa 2.3 channel activity but not the KCa 2.1 and KCa 3.1 subtypes.
Experimental Approach
Site-directed mutagenesis, patch-clamp recordings and in silico modeling were utilized to explore the structural determinants for the subtype-selective modulation of KCa 2 channels by CyPPA.
Key Results
Mutating residues in the HA (V420) and HB (K467) helices of KCa 2.2a channels to their equivalent residues in KCa 3.1 channels diminished the potency of CyPPA. CyPPA elicited prominent responses on mutant KCa 3.1 channels with an arginine residue in the HB helix substituted for its equivalent lysine residue in the KCa 2.2a channels (R355K). KCa 2.1 channels harboring a three-amino-acid insertion upstream of the cognate R438 residues in the HB helix showed no response to CyPPA, whereas the deletion mutant (KCa 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 KCa 2.2a channels.
Conclusion and Implications
Selectivity of CyPPA among KCa 2 and KCa 3.1 channel subtypes relies on the HA/HB helices.
Recommended Citation
Nam, Y-W, Cui, M, Salem, N, et al. Subtype-selective positive modulation of KCa 2 channels depends on the HA/HB helices. Br J Pharmacol. 2021;179(3):460-472. https://doi.org/10.1111/bph.15676
Copyright
British Pharmacological Society
Included in
Amino Acids, Peptides, and Proteins Commons, Medical Biochemistry Commons, Medicinal and Pharmaceutical Chemistry Commons, Other Pharmacy and Pharmaceutical Sciences Commons
Comments
This is the accepted version of the following article:
Nam, Y-W, Cui, M, Salem, N, et al. Subtype-selective positive modulation of KCa 2 channels depends on the HA/HB helices. Br J Pharmacol. 2021;179(3):460-472. https://doi.org/10.1111/bph.15676
which has been published in final form at https://doi.org/10.1111/bph.15676 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.