The GoSlo family of BK channel activators: A no-go for γ subunits?

Large conductance Ca2C-activated KC channels (slo, MaxiK or BK channels) play fundamental physiological roles in a large variety of tissues including nerve, muscle and endocrine cells. BK open probability is controlled synergistically by transmembrane voltage and concentration of intracellular Ca2C. This intrinsic property enables them to act as couplers of Ca2C and membrane voltage signaling, providing a negative feedback mechanism controlling Ca2C influx to the cell. Consequently, BK channels are key regulators of neuronal action potential firing, neurotransmitter release or smooth muscle contractile tone. Inherited defects in BK channels function lead to disease including seizure and epilepsy, urinary incontinence or high blood pressure. Many years of research have contributed significantly to our understanding of the molecular basis of BK channels gating and ion conduction, as well as the regulation of channel function in different cell types and tissues. These advances were paralleled by a growing interest in developing BK channel openers due to their therapeutic potential in disorders characterized by hyperexcitability and smooth muscle dysfunction. The therapeutic interest of several natural and synthetic compounds has been amply described in the literature as the basis of potential treatment strategies for epilepsy, ischemic heart disease, pulmonary disease, erectile dysfunction and bladder instability. Among them is a series of anilinoanthraquinone analogs (the GoSlo-SR family), described as potent activators of BK channels in bladder smooth muscle cells, now further characterized by Kshatri et al. Despite the large number of pre-clinical and basic research studies, the clinical relevance of BK channel activators remains unclear. This lack of success relays partly in the poor selectivity of the compounds to target channels at specific tissues in vivo, which may ultimately be due to their ubiquitous expression and functional diversity. The tissue-specific functional diversity of BK channels arises from different mechanisms, including alternative splicing, post-translational modifications or metabolic regulation. Furthermore, association of the pore-forming a subunits with tissue-specific regulatory subunits affects Ca2Cand voltage-sensitivity of the channels, and their pharmacology. Coexpression of one of 4 different b subunits with BKa explains to a large extent the characteristics of the BK currents observed in the specific tissues where b subunits are expressed (e.g. b1 is mainly found in muscle and b4 in brain). Only a few years ago, a novel family of regulatory subunits (g) was reported, with a predicted topology of a single transmembrane domain and a characteristic leucine-rich repeat (LRR) extracellular domain. All four members of the g-subunit family induce shifts in BK channel’s voltage dependence of activation to different extents, resulting in large channel open probabilities even at resting potential and physiological intracellular Ca2C concentrations. Similarly to b subunits, g subunits show tissue-specific expression patterns. In the search for new BK channel activators it is thus essential to take into account the composition of native channels in different tissues. Pharmacology must be assessed not only in BKa hometramers, but also in BK heteromers containing regulatory subunits. Specificity must be studied in all plausible combinations with physiological relevance. Bearing this in mind, Kshatri et al