Voltage- and Ca(2+)-activated K(+) channels of big conductance (BK channels) are abundantly found in various organs and their relevance for smooth muscle tone and neuronal signaling is well documented. Dysfunction of BK channels is implicated in an array of human diseases involving many organs including the nervous, pulmonary, cardiovascular, renal, and urinary systems. In humans a single gene (KCNMA1) encodes the pore-forming α subunit (Slo1) of BK channels, but the channel properties are variable because of alternative splicing, tissue- and subcellular-specific auxiliary subunits (β, γ), posttranslational modifications, and a multitude of endogenous signaling molecules directly affecting the channel function. Initiatives to develop drugs capable of activating BK channels (channel openers) therefore need to consider the tissue-specific variability of BK channel structure and the potential interference with endogenously produced regulatory factors. The atomic structural basis of BK channel function is only beginning to be revealed. However, building on detailed knowledge of BK channel function, including its single-channel characteristics, voltage- and Ca(2+) dependence of channel gating, and modulation by diffusible messengers, a multi-tier allosteric model of BK channel gating (Horrigan and Aldrich (HA) model) has become a valuable tool in studying modulation of the channel. Using the conceptual framework of the HA model, we here review the functional impact of endogenous modulatory factors and select small synthetic compounds that regulate BK channel activity. Furthermore, we devise experimental approaches for studying BK channel-drug interactions with the aim to classify BK-modulating substances according to their molecular mode of action.
Keywords: Allosteric modulation; Channel gating; Channel openers; Gating modifiers; Horrigan–Aldrich (HA) model; Mode of drug action.
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