Calcium‐ and Voltage‐Gated Potassium (BK) Channel Activators in the 5β‐Cholanic Acid‐3α‐ol Analogue Series with Modifications in the Lateral Chain

Bukiya, Anna N.; Patil, Shivaputra A.; Li, Wei; Miller, Duane D.; Dopico, Alex M.

doi:10.1002/cmdc.201200290

Cited by 15 publications

(10 citation statements)

References 51 publications

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“…1A, bottom structure) as the lead compound. This compound is not a steroid, yet it contains all the structural features previously identified as necessary for cholane steroid activation of BK channels: C3-hydroxyl, hydrophobic nucleus and polar lateral chain (Dopico et al, 2002;Bukiya et al, 2008aBukiya et al, , 2012. The highly hydrophobic methyl 3-hydroxyolean-12-en-30-oate required dissolution in pure DMSO before further dissolution in saline solutions for biologic evaluation.…”

Section: Resultsmentioning

confidence: 99%

Cerebrovascular Dilation via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1-Subunit by a Novel Nonsteroidal Agent

et al. 2013

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The Ca 21 /voltage-gated K 1 large conductance (BK) channel b1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK b1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK b1 site that includes Thr169. Whether exogenous nonsteroidal agents can access this site to selectively activate b1-containing BK channels and evoke vasodilation remain unknown. We performed a chemical structure database similarity search using LCA as a template, along with a two-step reaction to generate sodium 3-hydroxyolean-12-en-30-oate (HENA). HENA activated the BK (cbv1 1 b1) channels cloned from rat cerebral artery myocytes with a potency (EC 50 5 53 mM) similar to and an efficacy (Â2.5 potentiation) significantly greater than that of LCA.This HENA action was replicated on native channels in rat cerebral artery myocytes. HENA failed to activate the channels made of cbv1 1 b2, b3, b4, or b1T169A, indicating that this drug selectively targets b1-containing BK channels via the BK b1 steroid-sensing site. HENA (3-45 mM) dilated the rat and C57BL/ 6 mouse pressurized cerebral arteries. Consistent with the electrophysiologic results, this effect was larger than that of LCA. HENA failed to dilate the arteries from the KCNMB1 knockout mouse, underscoring BK b1's role in HENA action. Finally, carotid artery-infusion of HENA (45 mM) dilated the pial cerebral arterioles via selective BK-channel targeting. In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates b1-containing BK channels by targeting the steroid-sensing site in BK b1, rendering vasodilation.

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Section: Resultsmentioning

confidence: 99%

Cerebrovascular Dilation via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1-Subunit by a Novel Nonsteroidal Agent

et al. 2013

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“…The earliest reported activator, dehydrosoyasaponin-I (DHS-I, the potent compounds extracted from Desmodium adscendens ) activates BK channels only when coexpressed with the β1 subunit in Xenopus oocytes (McManus et al, 1993, 1995), and such β1-dependent activation was also observed in smooth muscle membranes (Bukiya, Patil, Li, Miller, & Dopico, 2012). The xenoestrogen, tamoxifen, and the endogenous steroid hormone 17β-estradiol were also found to activate the BK channel in a β1- dependent manner (De Wet et al, 2006; Dick, Rossow, Smirnov, Horowitz, & Sanders, 2001; Duncan, 2005; Valverde et al, 1999).…”

Section: Modulation Of the Bk Channel's Pharmacological Propertiesmentioning

confidence: 99%

Modulation of BK Channel Function by Auxiliary Beta and Gamma Subunits

Yan

2016

International Review of Neurobiology

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The large-conductance, Ca2+- and voltage-activated K+ (BK) channel is ubiquitously expressed in mammalian tissues and displays diverse biophysical or pharmacological characteristics. This diversity is in part conferred by channel modulation with different regulatory auxiliary subunits. To date, two distinct classes of BK channel auxiliary subunits have been identified: β subunits and γ subunits. Modulation of BK channels by the four auxiliary β (β1–β4) subunits has been well established and intensively investigated over the past two decades. The auxiliary γ subunits, however, were identified only very recently, which adds a new dimension to BK channel regulation and improves our understanding of the physiological functions of BK channels in various tissues and cell types. This chapter will review the current understanding of BK channel modulation by auxiliary β and γ subunits, especially the latest findings.

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“…A triterpene glycoside was the first and most potent activator to be identified at nanomolecular (100 nM) concentrations, causing an 80 mV lefward shift in V 1/2 and an increase in open probability by means of a direct mechanism (Giangiacomo et al, 1998 ). The identification of this effect in smooth muscle membranes has led to report that such activation depends on the expression of the β1 subunit, although it is unclear whether this effect is determined by other subunits as well (Bukiya et al, 2012 ).…”

Section: The Role Of β Subunits In Bk Channel Pharmacologymentioning

confidence: 99%

Pharmacological consequences of the coexpression of BK channel Î± and auxiliary Î² subunits

2014

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Coded by a single gene (Slo1, KCM) and activated by depolarizing potentials and by a rise in intracellular Ca2+ concentration, the large conductance voltage- and Ca2+-activated K+ channel (BK) is unique among the superfamily of K+ channels. BK channels are tetramers characterized by a pore-forming α subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K+ channels) and a large C terminus composed of two regulators of K+ conductance domains (RCK domains), where the Ca2+-binding sites reside. BK channels can be associated with accessory β subunits and, although different BK modulatory mechanisms have been described, greater interest has recently been placed on the role that the β subunits may play in the modulation of BK channel gating due to its physiological importance. Four β subunits have currently been identified (i.e., β1, β2, β3, and β4) and despite the fact that they all share the same topology, it has been shown that every β subunit has a specific tissue distribution and that they modify channel kinetics as well as their pharmacological properties and the apparent Ca2+ sensitivity of the α subunit in different ways. Additionally, different studies have shown that natural, endogenous, and synthetic compounds can modulate BK channels through β subunits. Considering the importance of these channels in different pathological conditions, such as hypertension and neurological disorders, this review focuses on the mechanisms by which these compounds modulate the biophysical properties of BK channels through the regulation of β subunits, as well as their potential therapeutic uses for diseases such as those mentioned above.

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Calcium‐ and Voltage‐Gated Potassium (BK) Channel Activators in the 5β‐Cholanic Acid‐3α‐ol Analogue Series with Modifications in the Lateral Chain

Cited by 15 publications

References 51 publications

Cerebrovascular Dilation via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1-Subunit by a Novel Nonsteroidal Agent

Cerebrovascular Dilation via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1-Subunit by a Novel Nonsteroidal Agent

Modulation of BK Channel Function by Auxiliary Beta and Gamma Subunits

Pharmacological consequences of the coexpression of BK channel Î± and auxiliary Î² subunits

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