Regulation of BK Channel Activity by Cholesterol and Its Derivatives

Bukiya, Anna N.; Dopico, Alejandro M.

doi:10.1007/978-3-030-04278-3_3

Cited by 20 publications

(18 citation statements)

References 102 publications

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“…Membrane microachitecture can provide a platform for regulating the activity of many membrane proteins, both directly and indirectly. For example, membrane characteristics such as lipid makeup, bilayer thickness, and cholesterol content have all been shown to modulate the activity of the BK channel (reviewed in [ 33 , 34 ]), which is a well characterized ethanol target (reviewed in [ 35 , 36 ]). In addition, membrane microdomains such as lipid rafts can regulate the access of proteins to effector molecules, thereby affecting their activity [ 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

et al. 2020

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Background SWI/SNF chromatin remodeling genes are required for normal acute responses to alcohol in C. elegans and are associated with alcohol use disorder in two human populations. In an effort to discover the downstream genes that are mediating this effect, we identified SWI/SNF-regulated genes in C. elegans. Results To identify SWI/SNF-regulated genes in adults, we compared mRNA expression in wild type and swsn-1(os22ts) worms under conditions that produce inactive swsn-1 in mature cells. To identify SWI/SNF-regulated genes in neurons, we compared gene expression in swsn-9(ok1354) null mutant worms that harbor a neuronal rescue or a control construct. RNA sequencing was performed to an average depth of 25 million reads per sample using 50-base, paired-end reads. We found that 6813 transcripts were significantly differentially expressed between swsn-1(os22ts) mutants and wild-type worms and 2412 transcripts were significantly differentially expressed between swsn-9(ok1354) mutants and swsn-9(ok1354) mutants with neuronal rescue. We examined the intersection between these two datasets and identified 603 genes that were differentially expressed in the same direction in both comparisons; we defined these as SWI/SNF-regulated genes in neurons and in adults. Among the differentially expressed genes was cbp-1, a C. elegans homolog of the mammalian CBP/p300 family of histone acetyltransferases. CBP has been implicated in the epigenetic regulation in response to alcohol in animal models and a polymorphism in the human CBP gene, CREBBP, has been associated with alcohol-related phenotypes. We found that cbp-1 is required for the development of acute functional tolerance to alcohol in C. elegans. Conclusions We identified 603 transcripts that were regulated by two different SWI/SNF complex subunits in adults and in neurons. The SWI/SNF-regulated genes were highly enriched for genes involved in membrane rafts, suggesting an important role for this membrane microdomain in the acute alcohol response. Among the differentially expressed genes was cbp-1; CBP-1 homologs have been implicated in alcohol responses across phyla and we found that C. elegans cbp-1 was required for the acute alcohol response in worms.

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Section: Discussionmentioning

confidence: 99%

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

et al. 2020

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“…These channels are located primarily in plasma membranes, where cholesterol makes up approximately 30% of the lipid molecules (2). The functions of many K þ channels vary with the cholesterol content of the membrane (3)(4)(5)(6). Kir channel activity generally decreases with increasing cholesterol content but sometimes increases (3,4,7,8), with effects being due to a shift between active and silent states (9) or to changes in open probability (7,8,10).…”

Section: Introductionmentioning

confidence: 99%

“…Effects of cholesterol on Kv channel function have proved rather controversial (11,12) and could follow from changes in single-channel conductance rather than from changes in open probability (13) or from effects on the stability of the open state (14). In-creases in cholesterol content have been reported to decrease the open probability of the Slo1 (BK) channel (6).…”

Section: Introductionmentioning

confidence: 99%

Interfacial Binding Sites for Cholesterol on Kir, Kv, K2P, and Related Potassium Channels

Lee

2020

Biophysical Journal

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Inwardly rectifying, voltage-gated, two-pore domain, and related K þ channels are located in eukaryotic membranes rich in cholesterol. Here, molecular docking is used to detect specific binding sites (''hot spots'') for cholesterol on K þ channels with characteristics that match those of known cholesterol binding sites. The transmembrane surfaces of all available high-resolution structures for K þ channels were swept for potential binding sites. Cholesterol poses were found to be located largely in hollows between protein ridges. A comparison between cholesterol poses and resolved phospholipids suggests that not all cholesterol molecules binding to the transmembrane surface of a K þ channel will result in displacement of a phospholipid molecule from the surface. Competition between cholesterol binding and binding of anionic phospholipids essential for activity could explain some of the effects of cholesterol on channel function.

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“…Because of its metabolic importance, cholesterol homeostasis is a highly regulated process in cells, and a disruption in that regulation is usually the cause of several pathologies. Alterations in cholesterol content in humans are related to the development of cardiovascular diseases (Dogan et al, 2019) (Bukiya and Dopico, 2019). Considering the physiological importance of cholesterol, our data contribute to understanding the effects of cholesterol homeostasis in the 17β-estradiol effect.…”

Section: Discussionmentioning

confidence: 78%

The Membrane Cholesterol Modulates the Interaction Between 17-βEstradiol and the BK Channel

2021

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BK channels are composed by the pore forming α subunit and, in some tissues, is associated with different accessory β subunits. These proteins modify the biophysical properties of the channel, amplifying the range of BK channel activation according to the physiological context. In the vascular cells, the pore forming BKα subunit is expressed with the β1 subunit, where they play an essential role in the modulation of arterial tone and blood pressure. In eukaryotes, cholesterol is a structural lipid of the cellular membrane. Changes in the ratio of cholesterol content in the plasma membrane (PM) regulates the BK channel activation altering its open probability, and hence, vascular contraction. It has been shown that the estrogen 17β-Estradiol (E2) causes a vasodilator effect in vascular cells, inducing a leftward shift in the V0.5 of the GV curve. Here, we evaluate whether changes in the membrane cholesterol concentration modify the effect that E2 induces on the BKα/β1 channel activity. Using binding and electrophysiology assays after cholesterol depletion or enrichment, we show that the cholesterol enrichment significantly decreases the expression of the α subunit, while cholesterol depletion increased the expression of that α subunit. Additionally, we demonstrated that changes in the membrane cholesterol cause the loss of the modulatory effect of E2 on the BKα/β1 channel activity, without affecting the E2 binding to the complex. Our data suggest that changes in membrane cholesterol content could affect channel properties related to the E2 effect on BKα/β1 channel activity. Finally, the results suggest that an optimal membrane cholesterol content is essential for the activation of BK channels through the β1 subunit.

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Regulation of BK Channel Activity by Cholesterol and Its Derivatives

Cited by 20 publications

References 102 publications

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

Interfacial Binding Sites for Cholesterol on Kir, Kv, K2P, and Related Potassium Channels

The Membrane Cholesterol Modulates the Interaction Between 17-βEstradiol and the BK Channel

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