The role of the beta 4‐subunit in determining the kinetic properties of rat neuronal nicotinic acetylcholine alpha 3‐receptors.

Papke, Roger L.; Heinemann, Stephen F.

doi:10.1113/jphysiol.1991.sp018698

Cited by 105 publications

(87 citation statements)

References 33 publications

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“…All told, experiments on individual patches lasted 30 Ϫ 45 min, with no detectable rundown. This is in contrast to some reports of nAChR single-channel recordings (e.g., Papke and Heinemann, 1991;Hsiao et al, 2008) and may be due to the low ACh concentrations used and the low inherent activity of ␣3␤2 receptors.…”

Section: Electrophysiological Recordings and Analysiscontrasting

confidence: 52%

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Wu¹,

Smith²,

Sine³

et al. 2008

Mol Pharmacol

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We studied allosteric potentiation of rat ␣3␤2 neuronal nicotinic acetylcholine receptors (nAChRs) by the anthelmintic compound morantel. Macroscopic currents evoked by acetylcholine (ACh) from nAChRs expressed in Xenopus laevis oocytes increase up to 8-fold in the presence of low concentrations of morantel (Յ10 M); the magnitude of the potentiation depends on both agonist and modulator concentrations. It is noteworthy that the potentiated currents exceed the maximum currents achieved by saturating (millimolar) concentrations of agonist. Studies of macroscopic currents elicited by prolonged drug applications (100 -300 s) indicate that morantel does not increase ␣3␤2 receptor activity by reducing slow (Ն1 s) desensitization. Instead, using outside-out patch-clamp recordings, we demonstrate that morantel increases the frequency of single-channel openings and alters the bursting characteristics of the openings in a manner consistent with enhanced channel gating; these results quantitatively explain the macroscopic current potentiation. Morantel is a very weak agonist alone, but we show that the classic competitive antagonist dihydro-␤-erythroidine inhibits morantel-evoked currents noncompetitively, indicating that morantel does not bind to the canonical ACh binding sites.nAChRs mediate rapid synaptic transmission throughout the central and peripheral nervous systems and are implicated in a wide range of important pathologic conditions, the most pervasive of which is nicotine addiction (e.g., Berrettini and Lerman, 2005). With recent advances in high-resolution structure determination (Brejc et al

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Section: Electrophysiological Recordings and Analysiscontrasting

confidence: 52%

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Wu¹,

Smith²,

Sine³

et al. 2008

Mol Pharmacol

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“…It has been reported previously that ␣3␤4 nAChRs expressed in oocytes exhibit different single channel conductances (32), which may be attributed to distinct receptor stoichiometries. Previous studies of ␣3␤4␤3 nAChRs have suggested that the subunit stoichiometry of the receptor is confined to 2␣:3␤ proportion and the (␣3) 2 (␤4) 3 stoichiometry had been postulated for the ␣3␤4 receptor (33).…”

Section: Discussionmentioning

confidence: 99%

α-Conotoxin AuIB Isomers Exhibit Distinct Inhibitory Mechanisms and Differential Sensitivity to Stoichiometry of α3β4 Nicotinic Acetylcholine Receptors

Grishin

Wang

Muttenthaler

et al. 2010

Journal of Biological Chemistry

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Non-native disulfide isomers of ␣-conotoxins are generally inactive although some unexpectedly demonstrate comparable or enhanced bioactivity. The actions of "globular" and "ribbon" isomers of ␣-conotoxin AuIB have been characterized on ␣3␤4 nicotinic acetylcholine receptors (nAChRs) heterologously expressed in Xenopus oocytes. Using two-electrode voltage clamp recording, we showed that the inhibitory efficacy of the ribbon isomer of AuIB is limited to ϳ50%. The maximal inhibition was stoichiometry-dependent because altering ␣3:␤4 RNA injection ratios either increased AuIB(ribbon) efficacy (10␣:1␤) or completely abolished blockade (1␣:10␤). In contrast, inhibition by AuIB(globular) was independent of injection ratios. ACh-evoked current amplitude was largest for 1:10 injected oocytes and smallest for the 10:1 ratio. ACh concentration-response curves revealed high (HS, 1:10) and low (LS, 10:1) sensitivity ␣3␤4 nAChRs with corresponding EC 50 values of 22.6 and 176.9 M, respectively. Increasing the agonist concentration antagonized the inhibition of LS ␣3␤4 nAChRs by AuIB(ribbon), whereas inhibition of HS and LS ␣3␤4 nAChRs by AuIB-(globular) was unaffected. Inhibition of LS and HS ␣3␤4 nAChRs by AuIB(globular) was insurmountable and independent of membrane potential. Molecular docking simulation suggested that AuIB(globular) is likely to bind to both ␣3␤4 nAChR stoichiometries outside of the ACh-binding pocket, whereas AuIB(ribbon) binds to the classical agonist-binding site of the LS ␣3␤4 nAChR only. In conclusion, the two isomers of AuIB differ in their inhibitory mechanisms such that AuIB(ribbon) inhibits only LS ␣3␤4 nAChRs competitively, whereas AuIB-(globular) inhibits ␣3␤4 nAChRs irrespective of receptor stoichiometry, primarily by a non-competitive mechanism.Conotoxins are short disulfide-rich bioactive peptides that have been originally isolated from venoms of carnivorous mollusk cone snails, belonging to the genus Conus. ␣-Conotoxins are among the largest class of conotoxins found in the venom of most cone snail species (1). This class of conotoxins targets various subtypes of nicotinic acetylcholine receptors (nAChRs) 2 and is distinguished by four cysteines arranged in a CC-C-C pattern.␣-Conotoxins have attracted considerable attention as some of them, such as Vc1.1 and RgIA, have been shown to possess analgesic activity in rodent behavioral models of neuropathic pain (2, 3). Interestingly, AuIB has recently been shown to be analgesic in vivo despite the fact that it acts on the ␣3␤4 nAChR subtype different from the ␣9␣10 nAChR targeted by Vc1.1 and RgIA.3 Vc1.1 and RgIA have been shown to suppress N-type Ca 2ϩ channel currents in dorsal root ganglion (DRG) neurons of neonatal and adult rats and wild type and ␣9 knock-out mice via activation of GABA B G protein-coupled receptors (2). Similarly, AuIB inhibits N-type Ca 2ϩ channels in rat DRG neurons analogous to Vc1.1 and RgIA and its effect can be blocked with selective GABA B receptor antagonists.4 GABA B -mediated inhibition of N-type Ca 2ϩ channels...

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“…Such desensitization properties are directly related to the subunit composition. For instance, within the neuronal hetero-oligomeric subfamily, an ␣i␤2 oligomer desensitizes much faster than an ␣i␤4 oligomer (Papke and Heinemann, 1991;Bohler et al, 2001). Similarly ␣3␤j oligomers desensitize faster than ␣2␤j and ␣4␤j receptors.…”

Section: Physiologic Modes Of Action Of Acetylcholinementioning

confidence: 99%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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The role of the beta 4‐subunit in determining the kinetic properties of rat neuronal nicotinic acetylcholine alpha 3‐receptors.

Cited by 105 publications

References 33 publications

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

α-Conotoxin AuIB Isomers Exhibit Distinct Inhibitory Mechanisms and Differential Sensitivity to Stoichiometry of α3β4 Nicotinic Acetylcholine Receptors

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

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