KCa-Related Neurological Disorders: Phenotypic Spectrum and Therapeutic Indications

Abstract

Although potassium channelopathies have been linked to a wide range of neurological conditions, the underlying pathogenic mechanism is not always clear, and a systematic summary of clinical manifestation is absent. Several neurological disorders have been associated with alterations of calcium-activated potassium channels (K_Ca channels), such as loss- or gain-of-function mutations, post-transcriptional modification, etc. Here, we outlined the current understanding of the molecular and cellular properties of three subtypes of K_Ca channels, including big conductance K_Ca channels (BK), small conductance K_Ca channels (SK), and the intermediate conductance K_Ca channels (IK). Next, we comprehensively reviewed the loss- or gain-of-function mutations of each K_Ca channel and described the corresponding mutation sites in specific diseases to broaden the phenotypic-genotypic spectrum of K_Ca-related neurological disorders. Moreover, we reviewed the current pharmaceutical strategies targeting K_Ca channels in K_Ca-related neurological disorders to provide new directions for drug discovery in anti-seizure medication.

Keywords: Potassium channels; action potential; channelopathies; epilepsy; modulators; pharmacology.

Fig. (1)

A topography of the BK channel with reported human mutation sites. (A) Each α-subunit of the BK channel has seven transmembrane domains (S0~S6), with the pore area between S5 and S6. A functional channel is made up of four of these subunits, with the C-terminus being one of the longest of all potassium channels. The C-terminus comprises two regulators of potassium conductance (RCK) domains, RCK1, and RCK2, which stack on top of one another to create a gating ring beneath the channel opening pore. (B) A single BK channel cry-EM subunit (PDB entry: 6V38). S0-S6 denote the transmembrane segments; Selectivity filter (SF) denotes the selectivity property; the two Ca²⁺ molecules that are coupled to the channel are represented in yellow. (C) GOF mutation sites are shown in blue, LOF mutation sites are in red mapped onto the BK channel structure and Ca²⁺ ions bound to the channel are shown in yellow circles. (B and C Copyright from 2022 [Jianmin Cui]. All Rights Reserved) [15].

Fig. (2)

A topography of the SK channel with reported human mutation sites. SK channel has six transmembrane domains (S1~S6), with the pore region between S5 and S6. Both the N-terminus and the C-terminus point toward the cytoplasm. The CaM binding site, protein kinase CK2 and protein phosphatase (PPP) binding sites are indicated by yellow, pink, and purple, respectively. GOF mutation sites are shown in blue.

Fig. (3)

Names and structures of BK, SK, and IK channel modulators.