Small-conductance Ca2+-activated K+ channels: insights into their roles in cardiovascular disease

Gu, Mingxia; Zhu, Yanrong; Xi, Yin; Zhang, Dai‐Min

doi:10.1038/s12276-018-0043-z

Cited by 30 publications

(28 citation statements)

References 56 publications

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“…SK channels have gained increasing interest during recent years, being considered as promising therapeutic targets for multiple diseases through a wide spectrum of therapeutic areas (Berthe et al, 2016; Gu et al, 2018; Kshatri et al, 2018). Since the discovery of the first specific SK inhibitor, apamin (Habermann, 1984), research efforts have been invested in the development and discovery of new molecules targeting SK channels.…”

Section: Discussionmentioning

confidence: 99%

“…These submicromolar changes in the intracellular calcium concentration are sensed by the protein calmodulin, which is covalently attached to the C-terminus of the channel (Adelman, 2016). The SK channel is now considered a promising novel target in a wide range of therapeutic areas such as cardiovascular (Gu et al, 2018), neurology (Kshatri et al, 2018), and oncology (Berthe et al, 2016). This interest has prompted the development of new molecules to both study and therapeutically target these channels.…”

Section: Introductionmentioning

confidence: 99%

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2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

et al. 2018

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A variety of polycyclic pyridines have been proposed as inhibitors of the small conductance calcium-activated potassium (SK) channel. To this group belongs 2,6-bis(2-benzimidazolyl)pyridine (BBP), a commercially and readily available small organic compound which has earlier been described in a broad range of chemical and biological uses. Here, we show how BBP can also be used as a potent and specific SK channel blocker in vitro. The potency of BBP was measured using automatic patch clamp on all three SK channel subtypes, resulting in similar IC50 of 0.4 μM. We also assessed the selectivity of BBP on a panel of calcium-activated and voltage-activated potassium channels using two-electrode voltage clamp, automatic and manual patch clamp. BBP did not have any effect on IK, Kir2.1, Kir3.1+Kir3.4, Kv1.5, Kv4.3/KCHIP2 and Kv7.1/KCNE1 currents and was 4.8-fold and 46-fold more potent on all SK channel subtypes vs. BK and hERG channels, respectively. Moreover, we were able to identify H491 as a critical amino acid for the pharmacological effect of BBP on the SK channel. From a medicinal chemistry perspective, BBP could be used as a starting point for the design of new and improved SK inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

et al. 2018

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“…SK channels have no charged amino acids in the fourth TM domain, which is usually an important component of a voltage sensor. SK channels are activated and deactivated solely as a consequence of Ca 2+ binding or release [45]. SK channels are heteromeric complexes that comprise pore-forming α subunits and the Ca 2+ -binding protein calmodulin (CaM) (Figure 2).…”

Section: Structures Of Sk and Ik Channelmentioning

confidence: 99%

“…CaM binds to and activates its target proteins in both Ca 2+ -replete and Ca 2+ -depleted forms. CaM mutants affect the interaction of CaM with its target proteins [45,46]. CaM binds to a highly conserved CaM-binding domain (CaMBD) residing within the C-terminus of the SK channels that is located immediately distal to the sixth transmembrane segment [47,48].…”

Section: Structures Of Sk and Ik Channelmentioning

confidence: 99%

Potassium Channels in the Vascular Diseases

Zhu¹,

Jiang²,

Ye³

et al. 2020

Vascular Biology - Selection of Mechanisms and Clinical Applications

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The vessel wall is an intricate structure composed of three layers: the intima (consisting of endothelial cells), media (consisting of smooth muscle cells and elastic fibers), and externa (consisting of the extracellular matrix scaffold). The homeostasis of the vasculature depends on the consistent function of each layer. In the vascular system, potassium channels are well known to regulate vascular function. The interactions between vascular conditions and membrane potential are complicated. In this chapter, we will focus on the functional regulation of KCa channel, K ATP channel, and K V channel in the vascular system. Researchers may continuously obtain insights into the functions of these channels and identify new therapeutic targets for vascular diseases.

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“…Calcium channels play a crucial role in different physiological processes including vaso‐dilation, neuronal excitability, myogenic response and mitochondrial calcium signaling . Moreover, these channels also have a role in the pathogenesis of many diseases including multiple sclerosis, diabetes, Alzheimer disease, cardiovascular diseases and neuropathic pain . Among the different types of voltage‐gated calcium channels, T‐type, and L‐type are widespread in the brain, spinal cord, dorsal root ganglia and nerves .…”

Section: Introductionmentioning

confidence: 99%

Pain attenuating actions of vincristinet‐preconditioning in chemotherapeutic agent‐induced neuropathic pain: key involvement of T‐type calcium channels

Sharma

Маслов

Singh

et al. 2019

Fundamemntal Clinical Pharma

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Preconditioning is a well-documented strategy that induces hepatic protection, renal protection, cardioprotection, and neuroprotection but its mechanism still remains to be elucidated. Hence, the present study investigated the protective mechanism underlying pain attenuating effects of vincristine-preconditioning in chemotherapeutic agent-induced neuropathic pain. Neuropathic pain was induced by administration of vincristine (50 µg/kg, i.p.) for 10 days in rats. Vincristine-preconditioning was induced by administration of vincristine (2, 5, and 10 µg/kg, i.p) for 5 days before administration of pain-inducing dose of vincristine (50 µg/kg, i.p.). Vincristine-preconditioning (10 µg/kg, i.p) for 5 days significantly reduced vincristine (50 µg/kg, i.p.) induced pain-related behaviors including paw cold allodynia, mechanical hyperalgesia, and heat hyperalgesia. However, vincristine (2 and 5 µg/kg, i.p) did not significantly ameliorate the vincristine (50 µg/kg, i.p.) induced neuropathic pain in rats. Furthermore, to explore the involvement of calcium channels in pain attenuating mechanism of vincristine-preconditioning, Ttype calcium channel blocker, ethosuximide (100 and 200 mg/kg, i.p.) and L-type calcium channel blocker, amlodipine (5 and 10 mg/kg, i.p.) were used. Pretreatment with T-type calcium channel blocker, ethosuximide significantly abolished vincristine-preconditioning-induced protective effect. However, pretreatment with L-type calcium channel blocker, amlodipine did not alter vincristine-preconditioning-induced pain-related behaviors. This indicates that vincristine-preconditioning has protective effect on pain-related parameters due to opening of calcium channels, particularly T-type calcium channels that lead to entry of small magnitude of intracellular calcium through these channels and prevent the deleterious effects of high-dose vincristine.

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Small-conductance Ca2+-activated K+ channels: insights into their roles in cardiovascular disease

Cited by 30 publications

References 56 publications

2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

Potassium Channels in the Vascular Diseases

Pain attenuating actions of vincristinet‐preconditioning in chemotherapeutic agent‐induced neuropathic pain: key involvement of T‐type calcium channels

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