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

Abstract

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.

Extracellular K+Dampens T Cell Functions: Implications for Immune Suppression in the Tumor Microenvironment

“…The K Ca 3.1 channel is of particular interest because selective pharmacological activators of this channel are being developed. 39,40 Furthermore, a defect in K Ca 3.1 channel activity limits the ability of CD8 + T cells from patients with head and neck cancers to infiltrate the adenosine-rich TME, and 1-EBIO, a nonselective K Ca 3.1 channel activator, restores chemotaxis in these cells. 40 The present study identifies a more selective K Ca 3.1 activator, SKA-346, and shows that it rescues high-[K + ] e -induced T cell suppression.…”

A Single Prior Injection of Methamphetamine Enhances Methamphetamine Self-Administration (SA) and Blocks SA-Induced Changes in DNA Methylation and mRNA Expression of Potassium Channels in the Rat Nucleus Accumbens

“…In addition, there are several drugs that are known activators or inhibitors of K + channels. Some of these agents that include chlorzoxazone, minoxidil, diazoxide, flupirtine, sulfonylureas are in clinical use in the US and/or Europe [65][66][67]. Given the lack of beneficial treatment for psychostimulant use disorders at this point in time, our results and those of others support the need to test potassium activators and/or inhibitors in preclinical models of cocaine and METH SA.…”

“…Taken together with previous results on the effects of cocaine and METH on K + channels [5,34,35], the present study suggests a role for K + channels as potential targets for therapeutic interventions in psychostimulant use disorders. There is, at present, a wealth of knowledge about the various roles of K + channels in the brain and periphery [66]. As mentioned above, these channels are localized in brain regions that play integral roles in learning, reward, and the development and maintenance of addictive states [16,29].…”

Ca2+ signalling in fibroblasts and the therapeutic potential of KCa3.1 channel blockers in fibrotic diseases

“…K + channel positive gating modulators shift the Ca 2+ activation curve concentration dependently towards a lower [Ca 2+ ] i concentration, thereby increasing the apparent Ca 2+ affinity, however they are unable to activate the channels in the absence of [Ca 2+ ] i (Brown et al, ). In physiological situations, rises in [Ca 2+ ] i are the dominant signal promoting K Ca 3.1 opening, but the development of clean pharmacological positive gating modulators has allowed useful manipulation of K Ca 3.1 in vitro.…”

“…Cryogenic electron microscopy has shown that in the absence of Ca 2+ , the K Ca 3.1 channel pore remains closed by maintaining the resting state. Specifically, CaM stays associated with the channel through its C-lobe, while the CaM N-lobe maintains only weak interactions with the channel and is K + channel positive gating modulators shift the Ca 2+ activation curve concentration dependently towards a lower [Ca 2+ ] i concentration, thereby increasing the apparent Ca 2+ affinity, however they are unable to activate the channels in the absence of [Ca 2+ ] i(Brown et al, 2020). In physiological situations, rises in [Ca 2+ ] i are the dominant signal promoting K Ca 3.1 opening, but the development of clean pharmacological positive gating modulators has allowed useful manipulation of K Ca 3.1 in vitro.…”