BK Channel Gating Mechanisms: Progresses Toward a Better Understanding of Variants Linked Neurological Diseases

Abstract

The large conductance Ca2+-activated potassium (BK) channel is activated by both membrane potential depolarization and intracellular Ca2+ with distinct mechanisms. Neural physiology is sensitive to the function of BK channels, which is shown by the discoveries of neurological disorders that are associated with BK channel mutations. This article reviews the molecular mechanisms of BK channel activation in response to voltage and Ca2+ binding, including the recent progress since the publication of the atomistic structure of the whole BK channel protein, and the neurological disorders associated with BK channel mutations. These results demonstrate the unique mechanisms of BK channel activation and that these mechanisms are important factors in linking BK channel mutations to neurological disorders.

An allosteric agonist activates BK channels by perturbing coupling between Ca2+ binding and pore opening

“…We performed a mutational scanning of selected residues on or in the vicinity of the allosteric pathway and found that the mutation T245W reduced, while E219R enhanced the sensitivity of the channel to Ca 2+ for activation 41 7). These results seem to suggest that the pathway through the VSD-CTD interface may make more contributions to Ca 2+ dependent activation.…”

“…2d). As summarized in sTable 2, the hydrophobic naphthalenyl group of BC5 was buried in contact with the intracellular side of S0, S1 BK channels are activated by voltage and Ca 2+ with distinctive mechanisms 7,14 . Does BC5 shift the GV relation of BK channels by modulating the mechanism of voltage or Ca 2+ dependent activation?…”

“…These results also suggest that potentially other sites along the allosteric pathways (Fig 4a, b) can be used for allosteric agonists or antagonists to modulate BK channel function. These sites can be targeted for the development of drug therapies for BK channel associated diseases such as neurological disorders associated with either gain-of-function or loss-of-function BK mutations 7 or the abnormal urinary bladder control 11 .…”

“…BK type Ca 2+ activated K + channels are important in regulating neural excitability [1][2][3] , neurotransmitter release 4 , and muscle contraction 5,6 . The aberrant function of BK channels is associated with various human diseases such as neurological disorders [7][8][9] , hypertension 10 and abnormal urinary control 11 . The function of BK channels is based on its activation by both elevated intracellular Ca 2+ and depolarization of the membrane voltage.…”

Evidence for Dual Activation of IK(M) and IK(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one)

“…The activity of these channels is abundantly and functionally distributed in an array of excitable and non-excitable cells. The regulation of such activity can play essential roles in various physiological or pathophysiological events, such as membrane excitability, neurotransmitter release, stimulus-secretion coupling, muscle relaxation, and pain sensation [40][41][42][43][44][45][46]. Moreover, some small molecules, such as BMS-204352, naringenin and QO-40, have been reported to activate I K(M) as well as to enhance the activity of BK Ca channels in excitable cells [9,47,48].…”