Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels

Annu Rev Pharmacol Toxicol. 2020 Jan 6:60:219-240. doi: 10.1146/annurev-pharmtox-010919-023420. Epub 2019 Jul 23.


The three small-conductance calcium-activated potassium (KCa2) channels and the related intermediate-conductance KCa3.1 channel are voltage-independent K+ channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. KCa2 and KCa3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of KCa channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule KCa2 and KCa3.1 modulators. Finally, we describe the progress that has been made in advancing KCa3.1 blockers and KCa2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges.

Keywords: KCa2.2; KCa2.3; KCa3.1; calcium-activated potassium channel; gating modulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Cardiovascular Diseases / drug therapy
  • Cardiovascular Diseases / physiopathology
  • Humans
  • Intermediate-Conductance Calcium-Activated Potassium Channels / drug effects*
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism
  • Nervous System Diseases / drug therapy
  • Nervous System Diseases / physiopathology
  • Potassium Channel Blockers / pharmacology
  • Small-Conductance Calcium-Activated Potassium Channels / drug effects*
  • Small-Conductance Calcium-Activated Potassium Channels / metabolism


  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Potassium Channel Blockers
  • Small-Conductance Calcium-Activated Potassium Channels