Acute Alcohol Action and Desensitization of Ligand-Gated Ion Channels

Dopico, Alex M.; Lovinger, David M.

doi:10.1124/pr.108.000430

Cited by 91 publications

(81 citation statements)

References 185 publications

(252 reference statements)

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“…At EtOH concentrations of 0.5-1%, various types of ion channels are affected, among them are BK channels and L-type VDCCs (9). The evidence for their involvement has been obtained in studies investigating neuronal or cardiovascular cells (4,9).…”

Section: Discussionmentioning

confidence: 99%

“…The effects of EtOH on BK channel activity can be stimulatory, inhibitory, or neither. The type of response depends on multivariable factors including the species examined, the tissue or cell type investigated, the molecular composition of BK channel subunits expressed, the EtOH concentration used, and temporal exposure (4,9,35,51). For example, in hypothalamic-neurohypophysial neurons, acute exposure to EtOH increased BK channel activity, whereas chronic 24-h treatment displayed much weaker effects (47).…”

mentioning

confidence: 99%

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Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca²⁺ channels

Malysz

Afeli

Provence

et al. 2014

American Journal of Physiology-Cell Physiology

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Malysz J, Afeli SA, Provence A, Petkov GV. Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca 2ϩ channels. Am J Physiol Cell Physiol 306: C45-C58, 2014. First published October 23, 2013 doi:10.1152/ajpcell.00047.2013.-Mechanisms underlying ethanol (EtOH)-induced detrusor smooth muscle (DSM) relaxation and increased urinary bladder capacity remain unknown. We investigated whether the large conductance Ca 2ϩ -activated K ϩ (BK) channels or L-type voltage-dependent Ca 2ϩ channels (VDCCs), major regulators of DSM excitability and contractility, are targets for EtOH by patch-clamp electrophysiology (conventional and perforated whole cell and excised patch single channel) and isometric tension recordings using guinea pig DSM cells and isolated tissue strips, respectively. EtOH at 0.3% vol/vol (ϳ50 mM) enhanced whole cell BK currents at ϩ30 mV and above, determined by the selective BK channel blocker paxilline. In excised patches recorded at ϩ40 mV and ϳ300 nM intracellular Ca 2ϩ concentration ([Ca 2ϩ ]), EtOH (0.1-0.3%) affected single BK channels (mean conductance ϳ210 pS and blocked by paxilline) by increasing the open channel probability, number of open channel events, and open dwell-time constants. The amplitude of single BK channel currents and unitary conductance were not altered by EtOH. Conversely, at ϳ10 M but not ϳ2 M intracellular [Ca 2ϩ ], EtOH (0.3%) decreased the single BK channel activity. EtOH (0.3%) affected transient BK currents (TBKCs) by either increasing frequency or decreasing amplitude, depending on the basal level of TBKC frequency. In isolated DSM strips, EtOH (0.1-1%) reduced the amplitude and muscle force of spontaneous phasic contractions. The EtOH-induced DSM relaxation, except at 1%, was attenuated by paxilline. EtOH (1%) inhibited L-type VDCC currents in DSM cells. In summary, we reveal the involvement of BK channels and L-type VDCCs in mediating EtOHinduced urinary bladder relaxation accommodating alcohol-induced diuresis. smooth muscle; patch-clamp; contractility; detrusor; alcohol URINARY BLADDER FUNCTION DEPENDS on the contractile status of detrusor smooth muscle (DSM) cells. DSM relaxation allows for bladder expansion during urine storage, whereas its contraction, coupled with the opening of the bladder sphincter, permits urine voiding (3). Multiple ion channels and receptors are expressed in DSM cells regulating bladder function. Among them, the large-conductance voltage-and Ca 2ϩ -activated K ϩ channels (also known as BK, Slo, or K Ca 1.1 channels) and L-type voltage-dependent Ca 2ϩ channels (VDCCs) are recognized as key regulators of excitability and contractility of DSM (44). Supporting data, provided for DSM studies using rat, guinea pig, mouse, and importantly human tissues and cells (5,17,18,22,24,25,46), demonstrate the role of BK channels in the regulation of the resting membrane potential, modulation of the repolarization phase of DSM action potentials, and generation of spontaneous transient BK currents (TBKCs)...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca²⁺ channels

Malysz

Afeli

Provence

et al. 2014

American Journal of Physiology-Cell Physiology

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“…On one hand, EtOH alters cholinergic modulations in neurotransmitter releases in the mesolimbic pathway. On the other hand, EtOH directly modulates nAChR expression, up or down regulation, and functions such as allosteric modulation, stabilization, desensitization or internalization [37] . Through these mechanisms, EtOH enhances mesolimbic DA signaling and consequently triggers reward and dependence.…”

Section: Cellular Mechanisms Of Nachr-mediated Etoh Reward and Dependmentioning

confidence: 99%

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

Gao

Taylor

2014

Acta Pharmacol Sin

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Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence. Alcoholism is a serious public health problem and has been identified as the third major cause of preventable mortality in the world. Worldwide, about 2 billion people consume alcohol, with 76.3 million having diagnosable alcohol use disorders. Alcohol is currently responsible for the death of 4% of adults worldwide (about 2.5 million deaths each year), and this number will be significantly increased by 2020 unless effective action is taken. Alcohol is the most commonly abused substance by humans. Ethanol (EtOH) is the intoxicating agent in alcoholic drinks that can lead to abuse and dependence. Although it has been extensively studied, the mechanisms of alcohol reward and dependence are still poorly understood. The major reason is that, unlike other addictive drugs (eg, morphine, cocaine or nicotine) that have specific molecular targets, EtOH affects much wider neuronal functions. These functions include phospholipid membranes, various ion channels and receptors, synaptic and network functions, and intracellular signaling molecules. The major targets in the brain that mediate EtOH's effects remain unclear. This knowledge gap results in a therapeutic barrier in the treatment of alcoholism. Interestingly, alcohol and nicotine are often co-abused, which suggests that neuronal nicotinic acetylcholine receptors (nAChRs), the molecular targets for nicotine, may also contribute to alcohol's abusive properties. Here, we briefly summarize recent lines of evidence showing how EtOH modulates nAChRs in the mesolimbic pathway, which provides a perspective that nAChRs are important targets mediating alcohol abuse.

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“…During the last decades it became clear that ethanol directly acts on proteins such as receptors and ion channels located in the plasma membrane or at intracellular signalling molecules. Experimental evidence revealed that some effects of ethanol are due to specific actions including most ligand-gated ion channels, such as glutamate-, -aminobutyric acid-(GABA) (Lobo & Harris 2008), dopamine-(Di Chiara & Imperato 1986), 5-hydroxytryptamine-, or acetylcholine-, opioid-, (Di Chiara et al 1996;Herz 1997;Gianoulakis 2009), adenosine-, ATP-(Asatryan et al, 2011Ostrovskaya et al, 2011), or TRP receptors (Benedikt et al, 2007, as well as voltage-gated ion channels, such as K + , Na + , and in particular Ca 2+ channels (Gonzales & Hoffman 1991;Crews et al, 1996b;Dopico et al 1996;Jakab et al 1997;Horishita & Harris 2008;Dopico & Lovinger 2009;Kerschbaum & Hermann 1997). Ethanol was also found to interact with signal-transduction mechanisms including Gproteins and protein kinases (Messing et al 1991;Lahnsteiner & Hermann 1995;Newton & Ron 2007;Martin 2010;Kelm et al 2011).…”

Section: Bk Channels -And Ethanol/acetaldehydementioning

confidence: 99%

“…www.intechopen.com Ca 2+ activated K + channels are among those channels being directly modulated by ethanol (in Brodie et al, 2007;Mulholland et al, 2009;Dopico & Lovinger 2009;Martin et al, 2010). Activation of K + channels drives the membrane potential in hyperpolarizing direction which led to the speculation that these channels may be involved in the sedative action of ethanol (Nicoll & Madison, 1982).…”

Section: Bk Channels -And Ethanol/acetaldehydementioning

confidence: 99%

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

Hermann¹,

Ситдикова²,

Weiger³

2012

Patch Clamp Technique

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Acute Alcohol Action and Desensitization of Ligand-Gated Ion Channels

Cited by 91 publications

References 185 publications

Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca²⁺ channels

Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca²⁺ channels

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

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Acute Alcohol Action and Desensitization of Ligand-Gated Ion Channels

Cited by 91 publications

References 185 publications

Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca2+ channels

Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca2+ channels

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

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Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca²⁺ channels

Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca²⁺ channels