Nicotinic acetylcholine receptor subunit mRNA expression and channel function in medial habenula neurons

Sheffield, Elise B.; Quick, Michael W.; Lester, Robin A. J.

doi:10.1016/s0028-3908(00)00138-6

Cited by 75 publications

(72 citation statements)

References 54 publications

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“…Low ␤4-subunit expression was found in the interpeduncular nucleus (49) where seizures might be initiated (10). The interpeduncular nucleus is a target for the medial habenula where ␤4 expression, along with ␣3-, ␣4-, and ␣5-subunit expression, were detected in nicotine-responsive cells and where receptors containing ␤4-and ␣3-subunits likely contribute to the major types of nAChR channels (17,46,51). Low mRNA expression levels of ␤4 were also detected in the inferior colliculus (49), another target of the medial habenula, which plays an important role in audiogenic seizures (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Kedmi

Beaudet

Orr-Urtreger

2004

Physiological Genomics

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Kedmi, Merav, Arthur L. Beaudet, and Avi Orr-Urtreger. Mice lacking neuronal nicotinic acetylcholine receptor ␤4-subunit and mice lacking both ␣5-and ␤4-subunits are highly resistant to nicotineinduced seizures. Physiol Genomics 17: 221-229, 2004. First published March 2, 2004 10.1152/physiolgenomics.00202.2003.-Nicotine, the main addictive component of tobacco, evokes a wide range of dose-dependent behaviors in rodents, and when administrated in high doses, it can induce clonic-tonic seizures. Nicotine acts through the nicotinic acetylcholine receptors (nAChRs). Mutations in the human ␣4-and the ␤2-nAChR subunit genes cause autosomal dominant nocturnal frontal lobe epilepsy. Using transgenic mice with mutations in nAChR subunits, it was demonstrated previously that the ␣4-, ␣5-, and ␣7-subunits are involved in nicotine-induced seizures. To examine the possibility that the ␤4-subunit is also involved in this phenotype, we tested mice with homozygous ␤4-subunit deficiency. The ␤4 null mice were remarkably resistant to nicotine-induced seizures compared with wild-type and ␣5 null mice. We also generated mice with double deficiency of both ␣5-and ␤4-nAChR subunits and demonstrated that they were more resistant to nicotine's convulsant effect than either the ␣5 or the ␤4 single mutant mice. In addition, the single ␣5 mutants and the double ␣5␤4-deficient mice exhibited a significantly shorter latency time to seizure than that of the wild-type mice. Our results thus show that ␤4-containing nAChRs have a crucial role in the pathogenesis of nicotine-induced seizures. Furthermore, by comparing multiple mutant mice with single and double subunit deficiency, we suggest that nicotinic receptors containing either ␣5-or ␤4-subunits are involved in nicotine-induced seizures and that receptors containing both subunits are likely to contribute to this phenomena as well. However, the ␣5-subunit, but not the ␤4-subunit, regulates the rate of response to high doses of nicotine.neuronal nicotinic acetylcholine receptor ␣5-and ␤4-subunits; knockout mice NICOTINE ACTS THROUGH THE nicotinic acetylcholine receptors (nAChRs) and can be toxic in high doses in mice, inducing tremors, seizures, and even death (41). The nAChRs are allosteric membrane proteins that belong to a large family of ligand-gated ion channels. Each receptor is composed of a combination of five subunits. To date, 12 neuronal subunits (␣2-␣10 and ␤2-␤4) have been identified (reviewed in Ref. 29). They are widely distributed in the central and peripheral nervous systems and are also expressed in nonneuronal cells (11,14,23,30,37).In humans, nAChRs are associated with a number of pathological conditions, including epilepsy (reviewed in Ref. 35). Mutations in the ␣4-and ␤2-subunit genes were associated with familial cases of autosomal dominant nocturnal frontal lobe epilepsy (15, 45, 52-54). In addition, genetic linkage was found between juvenile myoclonic epilepsy and the chromosomal region encompassing the ␣7-subunit gene (18).In mice, a genetic linkage was shown betw...

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Section: Discussionmentioning

confidence: 99%

Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Kedmi

Beaudet

Orr-Urtreger

2004

Physiological Genomics

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“…For example, the major component of desensitization of presumed ␣3␤4* receptors in rat medial habenula cells (Quick et al, 1999) by 300 M nicotine occurs with an exponential time constant, t Ϸ 200 ms (Lester and Dani, 1995) compared with t Ϸ 1-2 s for ␣3␤4* receptors expressed in HEK cells . This apparent discrepancy may be partially explained by the inclusion of an additional ␣5 subunit; ␣5␣3␤4 receptors desensitize approximately threefold faster (Gerzanich et al, 1998;Quick et al, 1999) than ␣3␤4 nAChRs, and ␣5 is often found associated with ␣3␤4 receptors (Conroy and Berg, 1995;Sheffield et al, 2000). Likewise, the coexpression of ␣5 increases the time course of de- sensitization of ␣4␤2 receptors (Ramirez-Latorre et al, 1996).…”

Section: Heteromeric ␣␤* Receptorsmentioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

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“…They can be stimulated with nicotinic agonists like epibatidine (Paterson and Nordberg, 2000), which has high affinity to several of these combinations (Parker et al, 1998). In the rat brain in vivo, neuronal Downloaded from cells in the medial habenula have been found to express mRNA for many of the different subunits, ␣3, ␣4, ␣5, ␣6, and ␣7, and ␤2, ␤3, and ␤4 (Sheffield et al, 2000). Thus, at least theoretically, the number of possible different nACh receptors in mHb is rather large.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, at least theoretically, the number of possible different nACh receptors in mHb is rather large. However, only a few of the possible combinations have until now been shown with certainty to be functional in the rat, i.e., ␣4␤2, which is widespread in the CNS, and ␣3␤4, which was first described in ganglia (Flores et al, 1996) and then also in the CNS (Quick et al, 1999) and the medial habenula (Sheffield et al, 2000). Many other combinations may be functional in vivo, but due to lack of compounds with selectivity for the different subunit combinations, their existence has been difficult to establish.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Epibatidine Binding to Medial Habenula: Potential Role in Analgesia

Plenge

Mellerup²,

Wörtwein³

2002

J Pharmacol Exp Ther

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The objective of the present study was to characterize a recently described binding site in the habenula, which has high affinity for [ 3 H]epibatidine and low affinity for nicotine and acetylcholine. We report that the extension of this binding area in coronal and horizontal sections corresponds to the anatomical extension of the medial habenula. The affinity (K D ) of the medial habenula receptors for [ 3 H]epibatidine was estimated to be 0.5 nM using an autoradiographic saturation assay, whereas the affinity of the binding site for nicotine and acetylcholine was estimated to be 5 and 8 M, respectively. The receptor density (B max ) in the medial habenula was estimated to be about 1100 fmol/mg wet weight using [ 3 H]epibatidine. The subunit composition of the "epibatidine receptor" was investigated by the ability of different compounds with affinity to various subtypes of nicotinic receptors to displace [ 3 H]epibatidine bound to the receptor. The results suggest that the receptor contains ␣3 subunits but that it is unlikely to be an ␣3␤4 nicotinic receptor.

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Nicotinic acetylcholine receptor subunit mRNA expression and channel function in medial habenula neurons

Cited by 75 publications

References 54 publications

Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Desensitization of neuronal nicotinic receptors

Characterization of Epibatidine Binding to Medial Habenula: Potential Role in Analgesia

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