Single‐Channel Analyses of Ethanol Modulation of Neuronal Nicotinic Acetylcholine Receptors

Zuo, Yi; Nagata, Keiichi; Yeh, Jay Z.; Narahashi, Toshio

doi:10.1097/01.alc.0000125349.99823.8a

Cited by 29 publications

(20 citation statements)

References 50 publications

(62 reference statements)

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Section: Discussionsupporting

confidence: 93%

“…Our findings pertaining to α4β2-nAChR that are consistent with other reports of the existence of two conductance states (Buisson and Bertrand, 2001, Curtis et al, 2002, Nelson et al, 2003, Zuo et al, 2004). Zuo et al found conductance values very similar to those described here (Zuo et al , 2004); however, many other studies described various conductance states of α4β2-nAChR different from our findings here. One conductance of 20 pS was described for the chick α4β2 nAChR (Ballivet et al, 1988, Cooper et al, 1991), whereas two different conductances (15 and 34 pS) were observed for the rat α4β2 nAChR (Papke et al , 1989) and Pereira et al reported two conductance states (18 and 30 pS) from chick α4β2 nAChR (Pereira et al , 1994).…”

Section: Discussionsupporting

confidence: 93%

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Roles of nicotinic acetylcholine receptor β subunit cytoplasmic loops in acute desensitization and single-channel features

et al. 2015

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To evaluate physiological roles of the large, second cytoplasmic loops (C2) situated between the M3 and M4 transmembrane domains of nicotinic acetylcholine receptor (nAChR) subunits. We have constructed chimeric β2 (β2χ) and β4 (β4χ) subunits in which the “nested” C2 domains (but not the “proximal” sequences of ~14 residues immediately adjacent to the M3 or M4 domains) of these β subunits were replaced by the corresponding sequence from the serotonin 5-HT3A receptor subunit. We previously reported that heterologously expressed nAChR containing α4 and β2χ subunits displayed a faster whole-cell current decay in its agonist response compared to responses of all-wild-type α4β2-nAChR. This suggests an unexpected, functional role for the C2 domain of the β2 subunit in α4β2-nAChR acute desensitization. Here we report that there also is faster desensitization of α4β4χ-nAChR relative to α4β4-nAChR stably and heterologously expressed in the human SH-EP1 cell-line. In addition, cell-attached, single channel recording shows that both acetylcholine-activated α4β2χ- and α4β4χ-nAChR have a significantly lower mean open probability, shorter mean open-time, and a longer mean closed-time than their fully wild-type counterparts while not having different conductance amplitudes. These findings reveal microscopic bases for the faster desensitization of α4*-nAChR containing chimeric instead of wild-type β subunits. Our findings also remain consistent with novel and unexpected roles of β subunit nested C2 domains in modulation of α4*-nAChR function.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Roles of nicotinic acetylcholine receptor β subunit cytoplasmic loops in acute desensitization and single-channel features

et al. 2015

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“…Ethanol enhanced ACh-elicited inward currents for several nAChR subtypes expressed in Xenopus oocytes, including α4β2 nAChRs (Cardoso et al, 1999). Single channel recordings from cells expressing cloned α4β2 nAChRs indicates that ethanol enhances ACh-induced currents by stabilizing the open state of the receptor (Zuo et al, 2004). ACh, presumably released from mesopontine axon terminals, is present in VTA slices and contributes to baseline α6* nAChR activity in VTA DA neurons (Drenan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Nicotine and ethanol cooperate to enhance ventral tegmental area AMPA receptor function via α6-containing nicotinic receptors

2015

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Nicotine+ethanol co-exposure results in additive and/or synergistic effects in the ventral tegmental area (VTA) to nucleus accumbens (NAc) dopamine (DA) pathway, but the mechanisms supporting this are unclear. We tested the hypothesis that nAChRs containing α6 subunits (α6* nAChRs) are involved in the response to nicotine+ethanol co-exposure. Exposing VTA slices from C57BL/6 WT animals to drinking-relevant concentrations of ethanol causes a marked enhancement of α-amino-3-hydroxy-5-methyl-isoxazolepropionic acid (AMPA) receptor (AMPAR) function in VTA neurons. This effect was sensitive to α-conotoxin MII (an α6β2* nAChR antagonist), suggesting that α6* nAChR function is required. In mice expressing hypersensitive α6* nAChRs (α6L9S mice), we found that lower concentrations (relative to C57BL/6 WT) of ethanol were sufficient to enhance AMPAR function in VTA neurons. Exposure of live C57BL/6 WT mice to ethanol also produced AMPAR functional enhancement in VTA neurons, and studies in α6L9S mice strongly suggest a role for α6* nAChRs in this response. We then asked whether nicotine and ethanol cooperate to enhance VTA AMPAR function. We identified low concentrations of nicotine and ethanol that were capable of strongly enhancing VTA AMPAR function when co-applied to slices, but that did not enhance AMPAR function when applied alone. This effect was sensitive to both varenicline (an α4β2* and α6β2* nAChR partial agonist) and α-conotoxin MII. Finally, nicotine+ethanol co-exposure also enhanced AMPAR function in VTA neurons from α6L9S mice. Together, these data identify α6* nAChRs as important players in the response to nicotine+ethanol co-exposure in VTA neurons.

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“…This action of ACh at mPFC layer VI pyramidal neurons contributes to the critical role of prefrontal cholinergic signaling to support optimal attention performance in situations requiring high attentional demand (Dalley et al, 2004; Parikh et al, 2007; Bailey et al, 2010; Howe et al, 2010; Guillem et al, 2011). Acute ethanol exposure increases ACh efficacy at α4β2* nAChRs (Aistrup et al, 1999; Cardoso et al, 1999; Zuo et al, 2004), whereas chronic ethanol exposure decreases α4β2* nAChR content (Robles and Sabriá, 2008; Hillmer et al, 2014) and may also decrease nAChR function in vivo (Majchrzak and Dilsaver, 1992). Chronic ethanol exposure during rat development impairs memory and attention in adulthood (Reyes et al, 1989; Nagahara and Handa, 1997; Woolfrey et al, 2005; Brys et al, 2014) and decreases the beneficial effects of nAChR stimulation to augment these mPFC-dependent functions (Nagahara and Handa, 1999).…”

Section: Introductionmentioning

confidence: 99%

Developmental Ethanol Exposure Leads to Long-Term Deficits in Attention and Its Underlying Prefrontal Circuitry

Louth

Bignell

Taylor

et al. 2016

eNeuro

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Chronic prenatal exposure to ethanol can lead to a spectrum of teratogenic outcomes that are classified in humans as fetal alcohol spectrum disorders (FASD). One of the most prevalent and persistent neurocognitive components of FASD is attention deficits, and it is now thought that these attention deficits differ from traditional attention deficit hyperactivity disorder (ADHD) in their quality and response to medication. However, the neuronal mechanisms underlying attention deficits in FASD are not well understood. We show here that after developmental binge-pattern ethanol exposure, adult mice exhibit impaired performance on the five-choice serial reaction time test for visual attention, with lower accuracy during initial training and a higher rate of omissions under challenging conditions of high attention demand. Whole-cell electrophysiology experiments in these same mice find dysregulated pyramidal neurons in layer VI of the medial prefrontal cortex, which are critical for normal attention performance. Layer VI neurons show decreased intrinsic excitability and increased responses to stimulation of both nicotinic acetylcholine receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. Moreover, although nicotinic acetylcholine responses correlate with performance on the five-choice task in control mice, these relationships are completely disrupted in mice exposed to ethanol during development. These findings demonstrate a novel outcome of developmental binge-pattern ethanol exposure and suggest that persistent alterations to the function of prefrontal layer VI neurons play an important mechanistic role in attention deficits associated with FASD.

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Single‐Channel Analyses of Ethanol Modulation of Neuronal Nicotinic Acetylcholine Receptors

Abstract: These changes in single-channel parameters indicate that ethanol stabilizes the alpha4beta2 receptor-channel in the opening state, explaining how the maximum acetylcholine-induced whole-cell currents are further potentiated by ethanol.

Cited by 29 publications

References 50 publications

Roles of nicotinic acetylcholine receptor β subunit cytoplasmic loops in acute desensitization and single-channel features

Roles of nicotinic acetylcholine receptor β subunit cytoplasmic loops in acute desensitization and single-channel features

Nicotine and ethanol cooperate to enhance ventral tegmental area AMPA receptor function via α6-containing nicotinic receptors

Developmental Ethanol Exposure Leads to Long-Term Deficits in Attention and Its Underlying Prefrontal Circuitry

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