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Review
. 2018 Jul 30:11:258.
doi: 10.3389/fnmol.2018.00258. eCollection 2018.

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Aravind S Kshatri  1   2 , Alberto Gonzalez-Hernandez  1   2 , Teresa Giraldez  1   2
Affiliations
Review

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Aravind S Kshatri et al. Front Mol Neurosci. .

Abstract

Within the potassium ion channel family, calcium activated potassium (KCa) channels are unique in their ability to couple intracellular Ca2+ signals to membrane potential variations. KCa channels are diversely distributed throughout the central nervous system and play fundamental roles ranging from regulating neuronal excitability to controlling neurotransmitter release. The physiological versatility of KCa channels is enhanced by alternative splicing and co-assembly with auxiliary subunits, leading to fundamental differences in distribution, subunit composition and pharmacological profiles. Thus, understanding specific KCa channels' mechanisms in neuronal function is challenging. Based on their single channel conductance, KCa channels are divided into three subtypes: small (SK, 4-14 pS), intermediate (IK, 32-39 pS) and big potassium (BK, 200-300 pS) channels. This review describes the biophysical characteristics of these KCa channels, as well as their physiological roles and pathological implications. In addition, we also discuss the current pharmacological strategies and challenges to target KCa channels for the treatment of various neurological and psychiatric disorders.

Keywords: BK channels; IK channels; SK channels; drug discovery; modulators; nervous system; neurological disease.

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Figures

FIGURE 1
FIGURE 1
Topology and structures of SK/IK and BK channels. (A) Schematic protein topology of one SKα-subunit including the CaM bound to the CaMBD (represented as an orange hexagon). (B) Full-length structure of the Ca2+-CaM bound IK channel (PDB: 6CNN). The CaM N-lobe binds Ca2+ ions after association of CaM to the SK channel C-lobe. (C) Schematic topology of one BKα-subunit. Binding sites for divalent cations are located in the cytosolic C-terminal region of the channel. Each α subunit contains two high affinity Ca2+ binding sites (represented as green circles) and one low affinity Ca2+ and Mg2+ binding site, formed by residues from RCK1, S0–S1 and S2–S3 intracellular loops (purple circle). (D) Ca2+-bound BKα homotetramer full-length structure from Aplysia californica (PDB: 5TJ6).
FIGURE 2
FIGURE 2
Therapeutic benefits of either activation (left) or blockade (right) of KCa channels represented as a weighing scale. The heavier balance indicates the modulation (activation or blockade) that has been reported advantageous in a larger number of diseases. (A,C) In the case of SK and BK channels, activation shows more beneficial effects than inhibition. (B) For IK channels, pharmacological blockade has proven to be more advantageous than activation. For further information about the specific effects, see Tables and main text.
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