BK β1 subunit‐dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2

Kuntamallappanavar, Guruprasad; Dopico, Alejandro M.

doi:10.1111/bph.14046

Cited by 7 publications

(5 citation statements)

References 65 publications

(148 reference statements)

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“…Therefore, vascular SM BK channel activators are effective vasodilators, as reviewed in [93] while genetic ablation of the BK β1 subunit (e.g., in the KCNMB −/− mouse) is associated with increased myogenic tone [18]. Finally, β1 subunits embolden BK channels with distinct pharmacology, including channel activation by 17β-estradiol [180], micromolar levels of hydrophobic cholanes and their nonsteroidal analogs [22,23,29,132], leukotriene B4 [24], dehydrosoyasaponin-I [131], hydroclorothiazide [127], equol [203], tungstate [57], increased sensitivity to PIP 2 [179] and DHA [74,75], and ethanol-induced reduction of channel activity at low μM Ca 2+ ic [94,95]. The role of SM BK channels as pharmaco-therapeutic targets has been recently reviewed elsewhere [93,219].…”

Section: Basic Phenotype Of the Vascular Smooth Muscle Bk Channel Andmentioning

confidence: 99%

Calcium- and voltage-gated BK channels in vascular smooth muscle

Dopico

Bukiya

Jaggar

2018

Pflugers Arch - Eur J Physiol

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Ion channels in vascular smooth muscle regulate myogenic tone and vessel contractility. In particular, activation of calcium- and voltage-gated potassium channels of large conductance (BK channels) results in outward current that shifts the membrane potential toward more negative values, triggering a negative feed-back loop on depolarization-induced calcium influx and SM contraction. In this short review, we first present the molecular basis of vascular smooth muscle BK channels and the role of subunit composition and trafficking in the regulation of myogenic tone and vascular contractility. BK channel modulation by endogenous signaling molecules, and paracrine and endocrine mediators follows. Lastly, we describe the functional changes in smooth muscle BK channels that contribute to, or are triggered by, common physiological conditions and pathologies, including obesity, diabetes, and systemic hypertension.

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Section: Basic Phenotype Of the Vascular Smooth Muscle Bk Channel Andmentioning

confidence: 99%

Calcium- and voltage-gated BK channels in vascular smooth muscle

Dopico

Bukiya

Jaggar

2018

Pflugers Arch - Eur J Physiol

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“…We have previously documented the finding that EtOH inhibition of BK channels at physiological levels of Ca 2+ found in cerebrovascular myocytes requires the presence of modulatory, smooth muscle-abundant BK β1 subunits [ 25 ]. Moreover, the β1 subunit TM2 acts as a specific EtOH sensor [ 35 ]. In contrast, PREG-induced inhibition of these channels does not involve β1 regulatory proteins; instead, channel-forming α subunits suffice for steroid action [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

“…On the one hand, it has previously been shown by our group that smooth muscle BK channel inhibition and eventual MCA constriction are dependent on the presence of BK regulatory subunits of β1 type, which are abundant in cerebrovascular smooth muscle [ 25 , 32 ]. In particular, the TM2 domain of this accessory subunit serves as an alcohol sensor [ 35 ]. In contrast, PREG inhibits MCA smooth muscle BK channels and thus evokes constriction via its recognition by the channel-forming subunit [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

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Alcohol and pregnenolone interaction on cerebral arteries through targeting of vascular smooth muscle Ca2+- and voltage-gated K+ channels of big conductance

Shaw¹,

Moreira²,

Bukiya³

et al. 2023

Adv. Drug Alcohol Res.

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Despite the significant number of people who may be taking pregnenolone supplements while drinking alcohol (ethanol), the widely documented cerebrovascular actions of pregnenolone and ethanol, and the critical dependence of cerebrovascular function on cerebral artery diameter, there are no studies addressing the effect of pregnenolone + ethanol in combination on cerebral artery diameter. We investigated this by evaluating the effect of this combination on middle cerebral artery diameter in male and female C57BL/6J mice, both in vivo and in vitro. The use of de-endothelialized, in vitro pressurized middle cerebral artery segments allowed us to conduct a concentration-response study of constriction induced by pregnenolone ± ethanol, in which drug action could be evaluated independently of circulating and endothelial factors. In both male and female animals, pregnenolone at lower concentrations (≤1 µM) was found to synergize with 50 mM ethanol to cause vasoconstriction. In both sexes, this synergism was lost as one or both vasoconstrictors approached their maximally effective concentrations (75 mM and 10 µM for ethanol and pregnenolone, respectively), whether this was evaluated in vitro or in vivo using a cranial window. Vasoconstriction by pregnenolone + ethanol was abolished by 1 µM paxilline, indicating BK channel involvement. Moreover, cell-free recordings of BK channel activity in cerebral artery myocyte membranes showed that 10 µM pregnenolone and pregnenolone +50 mM ethanol reduced channel activity to an identical extent, suggesting that these drugs inhibit cerebrovascular BK channels via a common mechanism or mechanisms. Indeed, pregnenolone was found to disrupt allosteric coupling to Ca2+-driven gating, as previously reported for ethanol.

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“…In a rat model widely used to mimic human cerebral artery function, we previously demonstrated that cerebrovascular constriction evoked by 10–100 mM ethanol in vivo and in vitro involves drug-induced reduction of ionic current mediated by voltage-/calcium-gated, large conductance K + (BK) channels in the vascular smooth muscle (SM) (Liu et al, 2004; Bukiya et al, 2014). This inhibition may result from direct sensing of ethanol by the BK proteins (Bukiya et al, 2009; Kuntamallappanavar & Dopico, 2017) and/or BK channel modulation by ethanol-sensitive parties other than BK itself, e.g., ryanodine receptors (Ye et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Extra-endothelial TRPV1 channels participate in alcohol and caffeine actions on cerebral artery diameter

Chang

Bukiya

Dopico

2018

Alcohol

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Alcohol (ethyl alcohol; ethanol) and caffeine are the two most widely used psychoactive substances in the world. Caffeine and ethanol have both been reported to constrict cerebral arteries in several species, including humans. We have recently shown that application of 10 μM caffeine mixed with 50 mM ethanol to in vitro pressurized cerebral arteries of rat reduced ethanol-induced constriction. This effect was dependent on the presence of nitric oxide (NO•) and could be observed in de-endothelialized arteries supplied with the NO• donor sodium nitroprusside (SNP). The molecular target(s) of ethanol-caffeine interaction in cerebral arteries has remained unknown. In the present work, we used rat and mouse middle cerebral arteries (MCA) to identify the extra-endothelial effectors of NO•-mediated, caffeine-induced protection against ethanol-evoked arterial constriction. Constriction of intact MCA of rat by either 50 mM ethanol or 10 μM caffeine was ablated in the presence of a selective TRPV1 pharmacological blocker. TRPV1 pharmacological block, but not block of TRPA1, PKG or BK channels, removed caffeine-induced protection against ethanol-evoked rat MCA constriction, whether evaluated in arteries with intact endothelium or in SNP-supplemented, de-endothelialized arteries. In mouse arteries, caffeine-induced protection against ethanol-induced MCA constriction was significantly amplified, resulting into actual vasodilation, upon pharmacological block of TRPV1, and in TRPV1 knock-out arteries. Despite some species-specific differences, our study unequivocally demonstrates the presence of functional, extra-endothelial TRPV1 that participates in both endothelium-independent MCA constriction by separate exposure to ethanol or caffeine and caffeine-induced protection against ethanol-evoked MCA constriction.

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BK β1 subunit‐dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2

Cited by 7 publications

References 65 publications

Calcium- and voltage-gated BK channels in vascular smooth muscle

Calcium- and voltage-gated BK channels in vascular smooth muscle

Alcohol and pregnenolone interaction on cerebral arteries through targeting of vascular smooth muscle Ca2+- and voltage-gated K+ channels of big conductance

Extra-endothelial TRPV1 channels participate in alcohol and caffeine actions on cerebral artery diameter

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