Potassium channels are widely distributed integral proteins responsible for the effective and selective transport of K+ ions through the biological membranes. According to the existing structural and mechanistic differences, they are divided into several groups. All of them are considered important molecular drug targets due to their physiological roles, including the regulation of membrane potential or cell signaling. Among the pharmaceuticals of plant origin, which are potassium channel modulators, flavonoids appear as a powerful group of biologically active substances. It is caused by their well-documented anti-oxidative, anti-inflammatory, anti-mutagenic, anti-carcinogenic, and antidiabetic effects on human health.
ions per second) and selective transport of K+ ions across the biological membranes down their electrochemical gradient [1]. Although the
channels are related members of one protein family, they can be divided into several groups according to the structural and mechanistic differences [2,3,4,5]. First, one can discern the voltage-regulated channels (Kv) and the
-regulated K+ channels (KCa), being structurally distinguished by six transmembrane domains (TMDs). Another group is formed by the “leak”, which is the double pore K+ channels (K2P) composed of four TMDs. The last group is constituted by the inward rectifier potassium channels (Kir), having two TMDs. The activity of the K+ channels plays a pivotal role in a myriad of cellular processes, for instance, volume regulation, proliferation, hormone secretion, neurotransmitter release, and modulation of potential in electrically excitable and non-excitable cells [1]. Due to their fundamental physiological roles, they appear promising drug targets for many diseases ranging from cardiovascular, metabolic, and neurodegenerative disorders to cancers [6,7,8,9,10,11]. The potential therapeutic benefits of the potassium channels targeting by pharmacological agents depend on the efficacy, strength, and selectivity of the interaction between an active compound and a particular ion channel subtype. It is also challenging to introduce such a channel modulator, which would be delivered or act only within a pathological tissue and would not exhibit any harmful side effects.
Flavonoids comprise a wide group of polyphenolic compounds of plant origin, which exhibit anti-oxidative, anti-inflammatory, anti-mutagenic, and anti-carcinogenic properties, as well as the capability to regulate the functioning of key cellular enzymes [12][13][21,22]. Flavonoids can be divided into subclasses such as flavones, flavonols, flavanols, flavanones, isoflavones, anthocyanidins, and chalcones. Due to their ability to modulate cell physiology, they have a clinically proven positive impact in counteracting a plethora of health problems such as cardiovascular and metabolic diseases, or other inflammation-related pathologies, including cancers.
The flavonoids also influence the Kv7.1 channel, which contributes to the regulation of the repolarization phase of the cardiac action potential. Puerarin is an isoflavonoid found in the root of Pueraria Lobata, which is known from its anti-inflammatory, immunomodulatory, anti-cancer and cardioprotective properties [52][95]. In [53][43], it was demonstrated that the isoflavone, puerarin, effectively downregulates the channel activity via direct interaction with the channel protein. It was reported that this inhibitory effect (along with the blockade of the slow delayed rectifier current IKS) contributed to the prolongation of action potential duration, which can be beneficial in the case of treatment of cardiovascular diseases. It turns out that also naringenin exerts an inhibitory effect on this channel, with a mild impact of this flavonoid on the current [51]. Eventually, the studies performed by Kang et al. [54] revealed that also (−)-epigallocatechin-3-gallate [54] is a potent inhibitor of the Kv1.7 ion channel.IKS
current [45]. Eventually, the studies performed by Kang et al. [44] revealed that also (−)-epigallocatechin-3-gallate [44] is a potent inhibitor of the Kv1.7 ion channel. Quite recently, it has been discovered that another flavonoid, procyanidin B1, a natural compound extracted from the grape seed, is a potent inhibitor of the Kv10.1 channel (IC50 = 10 μM ), which is overexpressed in some tumors [55][96]. According to this work, targeting the Kv10.1 channel by procyanidin B1 can inhibit the proliferation of cancerous cells. Consequently, this compound is a promising agent for cancer treatment.The large-conductance voltage- and Ca2+-activated channels (BK) are ubiquitously expressed K+ channels being characterized by a large single-channel conductance (150–300 pS) [56]. They are considered important drug targets due to their important roles in many physiological processes, such as neural transmission, hearing, endocrine secretion, and smooth muscle contraction [57]. In addition, the mitochondrial BK channel variants (mitoBK) received great scientific interest in terms of the possibilities of their chemical modulation because of the involvement of these channels in the regulation of metabolism, including ATP synthesis as well as the pro-life and pro-death processes [58][59][60].+
channels being characterized by a large single-channel conductance (150–300 pS) [97]. They are considered important drug targets due to their important roles in many physiological processes, such as neural transmission, hearing, endocrine secretion, and smooth muscle contraction [98]. In addition, the mitochondrial BK channel variants (mitoBK) received great scientific interest in terms of the possibilities of their chemical modulation because of the involvement of these channels in the regulation of metabolism, including ATP synthesis as well as the pro-life and pro-death processes [99,100,101]. The impact of flavonoids on the functioning of the BK channels was extensively studied in recent years. The main inferences from those investigations are outlined in Figure 1.The Inward Rectifying Potassium Channels (Kir) belong to one of the structurally simplest ion channels group containing four identical subunits, each containing two membrane-spanning alpha helices. These channels allow ions to be transported more effectively into than out of the cell. They are responsible for the regulation of resting membrane potential. Thus, their function is mostly related to the modulation of cardiac and neural cells activity, insulin secretion, or epithelial K+ transport [72][155]. The Kir channels are expressed in many cell types: myocytes, neurons, blood cells, endothelial, glial cells, or oocytes [73][156]. The classification of the Kir channels family covers the groups Kir1–Kir7 together with their respective subgroups. Among the Kir channels, one can also distinguish the adenosine triphosphate (ATP)-dependent K+ channels (KATP, Kir6) and the G-protein regulated K+ channels (GIRK, Kir3). The structure of Kir channels lacks a proper voltage-sensing domain. Nevertheless, some representatives of the Kir family exert a bit stronger ‘’voltage dependence” than the others. In that aspect, Kir 2 channels, which are strongly rectifying ones (and consequently more sensitive to extracellular K+), deserve to be distinguished.
The flavonols represented by quercetin and rutin exert significant impact on Kir channels. Trezza et al. [74][159] examined the both modulators and 5-hydroxyflavone in the context of their possible impact on the ATP-sensitive Kir6.1 channel. They compared the experimental results of channels from Rat norvegicus aorta cells with molecular dynamics and docking calculations. All the compared results suggested that there was no effect on Kir6.1 caused by rutin, and significant downregulation in the case of quercetin and 5-hydroxyflavone, but only in the case of the closed channel conformation. The cardioprotective effect of flavonoids on rat myocytes through the regulation of mitochondrial ATP-sensitive potassium channels activity was also shown recently by Rameshrad et al. [75][160]. This research group studied a flavonol, morin, and postulated that its antioxidative effects are mediated by mitochondrial ATP-dependent potassium channels. The activity of Kir6.1 can be upregulated in the presence of isovitexin, which is obtained from the extract of Luehea divaricata Mart., according to [76][154]. This effect supports the regulation of mesenteric arteriolar tone.
Well-pronounced effects on the Kir channels (especially KATP channels) are also documented for a natural alkaloid, berberine (BBR), which is conditionally classified as an ’isoquinoline flavonoid’. BBR is frequently used in the Chinese and East Asian medicines [77][140]. Hua et al. confirmed the inhibition effect of BBR on ATP-sensitive channels [78][167]. The scholars postulated that the anti-arrhythmic and antidiabetic properties of berberine are related to the inhibition of potassium channels. The inhibitory effects of berberine were also investigated by Wang et al. [79][168]. The scholars characterized a similar anti-arrhythmic impact of BBR manifested by the reduction of action potential duration and the effective refractory period of ischemia. In contrast to BBR, a flavonoid from the anthocyanins-cyanidin caused the upreguation of Kir6.2 genes, which have potential implication in glucose sensitivity and its homeostasis [80][169].
Another isoflavonoid, puerarin, exerts an activating effect on the mitochondrial K+ ATP-regulated channels (mitoKATP), according to the results presented in [81][135]. That study concluded that the mitoKATP channel activation participated in the cardioprotection by puerarin. The activation of mitochondrial KATP channels also plays a crucial role in shaping the cardioprotective effects exerted by other flavonoids [82][175]. Among them, six natural compounds should be mentioned: (−)-epigallocatechin-3-gallate [83][176], theaflavin [84][177], proanthocyanidins [85][178], genistein [86][179], baicalein [87][180], and morin[75][160].
The two-pore domain potassium channels are widely distributed in excitable and non-excitable cells and are responsible for the background potassium conductance [88][89][185,186]. They are emerging drug targets in case of a.o. cardiovascular and neurological diseases [90][91][92][93][187,188,189,190].
Among the TREK subgroup of K2P channels, TREK-1 ( K2p2.1) and TRAAK (K2p4.1) are mainly expressed in the central nervous system (CNS), and TREK-2 ( K2p10.1) is expressed in both CNS and peripheral tissues [94][95][191,192]. TREK channels are activated by several stimuli, including biomolecules (e.g., riluzole, nitrous oxide, polyunsaturated fatty acids, and lysophospholipids). These modulators can contribute to the opening of TREKs under pathological conditions. Considering the effects of flavonoids’ administration, the neuroprotective properties of quercetin were demonstrated in [96][193].
Flavonoids are widely known for their beneficial health effects, which involve complex biochemical interactions with specific molecular targets, including potassium channels. Due to the fact that these transport proteins play important roles in shaping cardiac action potential as well as smooth muscle tone, their stimulation by flavonoids yields vasorelaxant and cardioprotective effects [63][82][97][98][99][100][81,148,175,198,199,200]. Nevertheless, these effects are not the only examples of the K+ channel-mediated physiological processes that are regulated by flavonoids, as presented in Figure 2.
channel modulation (with appropriate examples). The ↑ represents channels’ activation and ↓ denotes channels’ inhibition.