Natural Modulators of Large-Conductance Calcium-Activated Potassium Channels

Abstract

IntroductionAmong the different factors exerting an influence on the activity of the different classes of potassium (K + ) channels, a rise in the intracellular concentration of free calcium ions causes the activation of a family of channels, known as calcium-activated channels. Calcium-activated K + channels are further classified into three principal subtypes on the basis of their biophysical single channel conductance: probably, the most studied subtype is represented by the large-conductance calcium-activated K + channels, also known as BK, BK Ca or Maxi-K channels. Besides their calcium-dependent activation, BK channels possess also a voltage-operated mechanism, and this peculiarity accounts for the highly effective role of feed-back regulation against the rise of intracellular Ca 2+ and membrane depolarisation, promoting a massive outward flow of K + ions and leading to a membrane hyperpolarisation, i. e., to a stabilisation of the cell [1].As far as molecular structure is concerned, the BK channel is a tetrameric protein complex formed by four a subunits, shaping the channel pore. AbstractLarge-conductance calcium-activated potassium channels, also known as BK or Maxi-K channels, occur in many types of cell, including neurons and myocytes, where they play an essential role in the regulation of cell excitability and function. These properties open a possible role for BK-activators (also called BK-openers) and/or BK-blockers as effective therapeutic agents for different neurological, urological, respiratory and cardiovascular diseases. The synthetic benzimidazolone derivatives NS004 and NS1619 are the pioneer BK-activators and have represented the reference models which led to the design of several novel and heterogeneous synthetic BK-openers, while very few synthetic BK-blockers have been reported. Even today, the research towards identifying new BK-modulating agents is proceeding with great impetus and is giving an ever-increasing number of new molecules. Among these, also a handsome number of natural BK-modulator compounds, belonging to different structural classes, has appeared in the literature. The goal of this paper is to provide a possible simple classification of the broad structural heterogeneity of the natural BK-activating agents (terpenes, phenols, flavonoids) and blockers (alkaloids and peptides), and a concise overview of their chemical and pharmacological properties as well as potential therapeutic applications.

Critical role of large-conductance calcium- and voltage-activated potassium channels in leptin-induced neuroprotection of N-methyl-d-aspartate-exposed cortical neurons

“…2B) reversed leptin-induced neuroprotection in a dose-dependent manner; the EC 50 values were 38 ± 10 nM and 5 ± 2 nM, respectively, for Pax and Ibtx. Both these values are rather close to the reported EC 50 values for Pax- and Ibtx-induced BK channel blockade (about 10 nM for both; Nardi et al, 2003). A concentration of 100 nM of either drug completely prevented leptin neuroprotective effects in cortical neurons exposed to 100 μM NMDA ( P = 0.25 for Pax; P = 0.06 for Ibtx).…”

“…By contrast, leptin achieved similar neuroprotective effects in cortical neurons exposed in vitro to oxygen and glucose deprivation (OGD) when applied 15 minutes before or 180 minutes after the neurotoxic stimulus (Valerio et al, 2009), suggesting that the neuroprotective mechanisms triggered by leptin during OGD and NMDA displayed a differential time-dependence. Interestingly, Pax and Ibtx, two well-known BK channel inhibitors, completely counteracted leptin-induced neuroprotection; both drugs displayed EC 50s in the low nanomolar concentration range, consistent with their BK channel blocking actions (Nardi et al, 2003), and suggesting that BK channel opening is a crucial mechanism for leptin-induced neuroprotection during NMDA exposure. Consistent with this, the prototypical BK channel opener NS1619, similarly to leptin, also promoted neuroprotective effects; however, the selectivity of this compound for BK channels has been questioned (Gáspár et al, 2008), and additional molecular mechanisms such as the inhibition of voltage-dependent Ca 2+ channels (Sheldon et al, 1997), voltage-dependent K + channels, and K ATP channels (Edwards et al, 1994) have been called into play to explain NS1619-induced neuroprotection.…”

BK channel activators and their therapeutic perspectives

“…Natural occurring BK channel activators are found in herbs, roots, fungi, and leaves, and have been used in folk medicine for treatment of asthma and smooth muscle disorders (Nardi et al, 2003 ). Isolation of natural occurring compounds revealed several BK channel activators including DHS-I that was found to dramatically increase the open probability of smooth muscle BK channels when applied to the intracellular site (McManus et al, 1993 ).…”

BKCa Channels as Targets for Cardioprotection

“…The next group of non-peptide BK Ca channel inhibitors is a family of tremorgenic mycotoxins isolated from fungi and this group includes potent neurotoxin paxilline (PAX) [ 114 ]. Paxilline is the non-peptide neurotoxin most extensively used in research because of its high selectivity and reversibility of action, and capability of a 70% BK Ca channel current inhibition at a concentration as low as 10 nM (K i = 1.9 nM), and its site of action is located on the α-subunit and cytoplasmic side [ 115 , 116 ].…”