A molecular scheme for the reaction between acetylcholine and nicotinic channels

Franke, Christian; Parnas, H.; Hovav, G.; Dudél, J.

doi:10.1016/s0006-3495(93)81374-2

Cited by 90 publications

(129 citation statements)

References 40 publications

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“…It is possible that a7-Asp-266 is also involved in binding of nicotinic agonists to neuronal nicotinic receptors. Fluorescence studies and electron images have determined that the ligand binding site of muscle AChRs is located [25][26][27][28][29][30][31][32][33][34][35] A above the membrane surface (4,29). This distance is too great to consider it likely that the mutated residues were constituent of the ligand binding site, but the possibility of some long-distance effect on its structure cannot be fully discarded.…”

Section: Methodsmentioning

confidence: 99%

A single residue in the M2-M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors.

Campos‐Caro

Sala

Ballesta

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Section: Methodsmentioning

confidence: 99%

A single residue in the M2-M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors.

Campos‐Caro

Sala

Ballesta

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…9) were chosen based on previous publications on muscle nAChRs (Colquhoun and Sakmann, 1985;Franke et al, 1991Franke et al, , 1993. We started with the parameters from Colquhoun and Sakmann (1985):…”

Section: Jpetaspetjournalsorgmentioning

confidence: 99%

Dual Action of n-Butanol on Neuronal Nicotinic α4β2 Acetylcholine Receptors

Zuo

Yeh²,

Narahashi³

2002

J Pharmacol Exp Ther

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n-Alcohols exert a dual action on neuronal nicotinic acetylcholine (ACh) receptors with short-chain alcohols exhibiting potentiating action and long-chain alcohols exhibiting inhibitory action. n-Butanol lies at the transition point from potentiation to inhibition. To elucidate the mechanism of dual action of alcohols, the effects of n-butanol on the human ␣4␤2 ACh receptors expressed in the HEK293 cell line were analyzed in detail by the whole-cell patch-clamp technique. Prolonged applications of n-butanol evoked small currents with an EC 50 value of 230 Ϯ 90 mM and a Hill coefficient of 1.8 Ϯ 0.4. This current was blocked by either the ACh channel blocker mecamylamine or the receptor blocker dihydro-␤-erythroidine, indicating that butanol activated receptors as a partial agonist. As expected from its partial agonist action, n-butanol also modulated AChinduced currents in a concentration-dependent manner. Butanol at 300 mM potentiated currents induced by low concentrations of ACh (Յ30 M), while inhibiting the currents induced by high concentrations of ACh (100 -3000 M). In addition, butanol at a low concentration (10 mM) suppressed the currents evoked by 10 to 3000 M ACh, a result consistent with a channel-blocking action. Most features of n-butanol effects were satisfactorily simulated by a model in which butanol acts as a partial agonist and as a channel blocker.

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“…First, we assumed that ACh is a full agonist. Second, we assumed that desensitization is minimal in the absence of ACh (Franke et al 1993). Third, we assumed that the receptor has two serial desensitized states.…”

Section: S252f Enhances Slow Receptor Desensitizationmentioning

confidence: 99%

Two mutations linked to nocturnal frontal lobe epilepsy cause use‐dependent potentiation of the nicotinic ACh response

Figl

Viseshakul

Shafaee

et al. 1998

The Journal of Physiology

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Two mutations in the M2 region of the human á4 neuronal nicotinic subunit -á4(S248F) and á4(776ins3) -have been linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (Steinlein et al. 1995(Steinlein et al. , 1997. The á4(S248F) mutation is a serine to phenylalanine substitution at position 248 in the human á4 nicotinic subunit. The á4(776ins3) mutation is a 3-base pair insertion that adds a leucine at position 259 in the amino acid sequence of the human á4 subunit. Photo-affinity labelling and structurefunction experiments show that the M2 region of the nicotinic subunits forms the conducting pore of the receptor (reviewed in Karlin & Akabas, 1995). Thus, both ADNFLE mutations lie in the conducting pore of the nicotinic receptor. ADNFLE patients suffer from brief and occasionally violent nocturnal seizures . However, the physiological mechanism responsible for these seizures has not been established. Previous studies show that the predominant brain nicotinic receptor subtype is á4â2 (Whiting & Lindstrom, 1987;Flores et al. 1991;Whiting et al. 1991). Receptors formed by co-expressing á4(S248F) or á4(776ins3) subunits with wild-type (WT) â2 subunits in Xenopus oocytes (Weiland et al. 1996; Steinlein et al. 1997;Kuryatov et al. 1997) differ from the WT receptor in several ways but no common effects of the two mutations on the acetylcholine (ACh) response have been reported previously. To determine whether the ADNFLE mutations have any common effects on the ACh response, we constructed two rat homologues (S252F and +L264) of the human ADNFLE mutations á4(S248F) and á4(777ins3), co-expressed them with rat â2 subunits in Xenopus oocytes, and studied the properties of the expressed receptors. We also constructed the rat double mutation V247I:S252F, which combined the S252F mutation with a second V247I mutation that converted the only rat/human residue substitution in the á4 M2 region to the corresponding human residue. All three Journal of Physiology (1998) 1. We constructed rat homologues (S252F and +L264) of two human á4 nicotinic mutations -á4(S248F) and á4(777ins3) -that have been linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and co-expressed them with wild-type rat â2 subunits in Xenopus oocytes. 2. The S252F and +L264 mutations had three common effects on the ACh response. First, they caused use-dependent potentiation of the response during a train of brief 100 nÒ ACh pulses. Second, they delayed the rise times of the 5-15 nÒ (+L264) and 30 nÒ (S252F) ACh responses. Third, they reduced extracellular Ca¥-induced increases in the 30 ìÒ ACh response. 3. Beside these shared effects, the S252F mutation also reduced the channel burst duration measured from voltage-jump relaxations, enhanced steady-state desensitization and reduced the single-channel conductance. In contrast, the +L264 mutation prolonged the channel burst duration, did not affect desensitization and slightly increased single-channel conductance. Neither mutation affected the number of surface receptors measured b...

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A molecular scheme for the reaction between acetylcholine and nicotinic channels

Cited by 90 publications

References 40 publications

A single residue in the M2-M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors.

A single residue in the M2-M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors.

Dual Action of n-Butanol on Neuronal Nicotinic α4β2 Acetylcholine Receptors

Two mutations linked to nocturnal frontal lobe epilepsy cause use‐dependent potentiation of the nicotinic ACh response

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