Alcohol metabolite acetic acid activates BK channels in a pH-dependent manner and decreases calcium oscillations and exocytosis of secretory granules in rat pituitary GH3 cells

Shaidullov, Ilnar; Ermakova, Elizaveta V.; Gaifullina, Aisylu; Mosshammer, Anna; Yakovlev, A. V.; Weiger, Thomas; Hermann, Anton; Ситдикова, Г. Ф.

doi:10.1007/s00424-020-02484-0

Cited by 7 publications

(4 citation statements)

References 48 publications

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“…Given the acetate-induced response at NMDAR, calcium activation of BK channels is a potential mediator in this response and NMDAR-induced-BK-channel activation has been demonstrated . While BK channels can contribute to spike repolarization and AHP to reduce neuronal excitability, − they can oppositely increase neuronal excitability as well. ,− Ethanol , and its metabolite, acetic acid/acetate, have both been found to activate BK channels; however, the former involving ethanol in accumbens slice preparation lacked a control of inhibiting the in-slice ethanol metabolism. The ethanol enhancement of repolarization and shaping of action potentials in accumbens neurons may be due to the in-slice metabolism and production of acetic acid/acetate.…”

Section: Discussionmentioning

confidence: 99%

Ethanol Metabolite, Acetate, Increases Excitability of the Central Nucleus of Amygdala Neurons through Activation of NMDA Receptors

Chapp

Collins

Driscoll

et al. 2023

ACS Chem. Neurosci.

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The central nucleus of the amygdala (CeA) is a key brain region involved in emotional and stressor responses due to its many projections to autonomic regulatory centers. It is also a primary site of action from ethanol consumption. However, the influence of active metabolites of ethanol such as acetate on the CeA neural circuitry has yet to be elucidated. Here, we investigated the effect of acetate on CeA neurons with the axon projecting to the rostral ventrolateral medulla (CeA-RVLM), as well as quantified cytosolic calcium responses in primary neuronal cultures. Whole-cell patch-clamp recordings in brain slices containing autonomic CeA-RVLM neurons revealed a dosedependent increase in neuronal excitability in response to acetate. N-Methyl-D-aspartate receptor (NMDAR) antagonists suppressed the acetate-induced increase in CeA-RVLM neuronal excitability and memantine suppressed the direct activation of NMDAR-dependent inward currents by acetate in brain slices. We observed that acetate increased cytosolic Ca 2+ in a time-dependent manner in primary neuronal cell cultures. The acetate enhancement of calcium signaling was abolished by memantine. Computational modeling of acetic acid at NMDAR/NR1 glutamatergic and glycinergic sites suggests potential active site interactions. These findings suggest that within the CeA, acetate is excitatory at least partially through activation of NMDAR, which may underlie the impact of ethanol consumption on autonomic circuitry.

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Section: Discussionmentioning

confidence: 99%

Ethanol Metabolite, Acetate, Increases Excitability of the Central Nucleus of Amygdala Neurons through Activation of NMDA Receptors

Chapp

Collins

Driscoll

et al. 2023

ACS Chem. Neurosci.

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“…These results demonstrate that the lack of sensitivity of some K + channels to acute EtOH is not a reliable criterion to define their contribution to neuronal adaptation in binge drinking animals. Interestingly, ethanol metabolites, such as acetaldehyde and acetic acid, may also contribute to modulating potassium channels function as shown in GH3 cells where acetic acid activates BK channels, leading to membrane hyperpolarization, cessation of Ca2+ oscillations and decrease of growth hormone release ( Ghatta et al, 2007 ; Shaidullov et al, 2021 ).…”

Section: Binge Drinking Regulation Of Ion Channel Properties and Neur...mentioning

confidence: 99%

Modulation of neuronal excitability by binge alcohol drinking

Giménez-Gómez

Martin

2023

Front. Mol. Neurosci.

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Drug use poses a serious threat to health systems throughout the world. The number of consumers rises every year being alcohol the drug of abuse most consumed causing 3 million deaths (5.3% of all deaths) worldwide and 132.6 million disability-adjusted life years. In this review, we present an up-to-date summary about what is known regarding the global impact of binge alcohol drinking on brains and how it affects the development of cognitive functions, as well as the various preclinical models used to probe its effects on the neurobiology of the brain. This will be followed by a detailed report on the state of our current knowledge of the molecular and cellular mechanisms underlying the effects of binge drinking on neuronal excitability and synaptic plasticity, with an emphasis on brain regions of the meso-cortico limbic neurocircuitry.

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“…56 While BKchannels can contribute to spike repolarization and AHP to reduce neuronal excitability [57][58][59] they can oppositely increase neuronal excitability as well. [59][60][61][62] Ethanol 63,64 and its metabolite, acetic acid/acetate 46 have both been found to activate BK-channels, however the former involving ethanol in accumbens slice preparation lacked a control of inhibiting in-slice ethanol metabolism.…”

Section: Possible Involvement Of Large-conductance Ca 2+ and Voltage-gated K + Channels (Bkchannels) In Acetate Responsementioning

confidence: 99%

Local Metabolism of Ethanol to Acetic Acid/Acetate in the Central Nucleus of Amygdala Elicits Sympathoexcitatory Responses through Activation of NMDAR in Sprague Dawley Rats

Chapp

Huber

Driscoll

et al. 2020

Preprint

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Short chain fatty acid (SCFA) regulation of neuronal function remains an interesting but poorly understood area of research. The SCFA, acetic acid, the main component of vinegar and the major metabolite of ethanol has been directly linked to altering neuronal function. However, the underlying mechanisms as it relates to alcohol consumption and SCFA regulation of neuronal function have yet to be elucidated. Here we show that local metabolism of ethanol to acetic acid/acetate in the central nucleus of amygdala (CeA) activates glutamatergic N-methyl-D-aspartate receptors (NMDAR) in vivo causing a sympathoexcitatory response. External acetate and intracellular loading of acetic acid in CeA neurons increased neuronal excitability through activation of NMDAR. Furthermore, cultured neurons exposed to acetate showed increased cytosolic calcium which response was abolished by NMDAR antagonist and decreased pH. These findings suggest that acetic acid/acetate is an underestimated bioactive metabolite of ethanol that mediates some effects via an NMDAR-dependent mechanism in the brain. The link between the SCFA, acetic acid/acetate on increased neuronal excitability at least partially through NMDAR may provide a novel avenue for understanding alcohol, metabolic, cardiovascular and neurodegenerative disorders related to alterations in SCFA concentrations in the brain.

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Alcohol metabolite acetic acid activates BK channels in a pH-dependent manner and decreases calcium oscillations and exocytosis of secretory granules in rat pituitary GH3 cells

Cited by 7 publications

References 48 publications

Ethanol Metabolite, Acetate, Increases Excitability of the Central Nucleus of Amygdala Neurons through Activation of NMDA Receptors

Ethanol Metabolite, Acetate, Increases Excitability of the Central Nucleus of Amygdala Neurons through Activation of NMDA Receptors

Modulation of neuronal excitability by binge alcohol drinking

Local Metabolism of Ethanol to Acetic Acid/Acetate in the Central Nucleus of Amygdala Elicits Sympathoexcitatory Responses through Activation of NMDAR in Sprague Dawley Rats

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