Hidden function of neuronal nicotinic acetylcholine receptor β2 subunits in ganglionic transmission: comparison to α5 and β4 subunits

Wang, Ningshan; Orr-Urtreger, Avi; Chapman, Joab; Ergün, Yusuf; Rabinowitz, Ruth; Korczyn, Amos D.

doi:10.1016/j.jns.2004.11.050

“…Recent data with knockout mice have suggested that the majority of functional receptors in autonomic ganglia have ␣3␤4 subunit composition, sometimes coassembled with ␣5 (Wang et al, 2005). Our data show that the ␣3␤4␣5 receptors had greater sensitivity to hexamethonium than did the other potential ganglionic models, ␣3␤4, ␣3␤2, and ␣3␤2␣5 (Table 5).…”

supporting

confidence: 51%

Activation and Inhibition of Mouse Muscle and Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes

Papke

¹

,

Wecker²,

Stitzel³

2010

J Pharmacol Exp Ther

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Transgenic mouse models with nicotinic acetylcholine receptor (nAChR) knockouts and knockins have provided important insights into the molecular substrates of addiction and disease. However, most studies of heterologously expressed neuronal nAChR have used clones obtained from other species, usually human or rat. In this work, we use mouse clones expressed in Xenopus oocytes to provide a relatively comprehensive characterization of the three primary classes of nAChR: muscle-type receptors, heteromeric neuronal receptors, and homomeric ␣7-type receptors. We evaluated the activation of these receptor subtypes with acetylcholine and cytisine-related compounds, including varenicline. We also characterized the activity of classic nAChR antagonists, confirming the utility of mecamylamine and dihydro-␤-erythroidine as selective antagonists in mouse models of ␣3␤4 and ␣4␤2 receptors, respectively. We also conducted an in-depth analysis of decamethonium and hexamethonium on muscle and neuronal receptor subtypes. Our data indicate that, as with receptors cloned from other species, pairwise expression of neuronal ␣ and ␤ subunits in oocytes generates heterogeneous populations of receptors, most likely caused by variations in subunit stoichiometry. Coexpression of the mouse ␣5 subunit had varying effects, depending on the other subunits expressed. The properties of cytisine-related compounds are similar for mouse, rat, and human nAChR, except that varenicline produced greater residual inhibition of mouse ␣4␤2 receptors than with human receptors. We confirm that decamethonium is a partial agonist, selective for muscle-type receptors, but also note that it is a nondepolarizing antagonist for neuronal-type receptors. Hexamethonium was a relatively nonselective antagonist with mixed competitive and noncompetitive activity.

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“…); in contrast, no such effect was observed in mice that lack β 2 subunits (Wang et al. ). We can confirm the lack of effect of the β 2 subunit (at least in this respect) by showing that the increased potency of HM at inhibiting CAP amplitude was similar between α 5‐KO and α 5 β 2‐KO ganglia.…”

Section: Discussionmentioning

confidence: 96%

The role of the nAChR subunits α 5, β 2, and β 4 on synaptic transmission in the mouse superior cervical ganglion

Simeone

¹

,

Karch

²

,

Ciuraszkiewicz

³

et al. 2019

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Our previous immunoprecipitation analysis of nicotinic acetylcholine receptors ( nAChR s) in the mouse superior cervical ganglion ( SCG ) revealed that approximately 55%, 24%, and 21% of receptors are comprised of α 3 β 4, α 3 β 4 α 5, and α 3 β 4 β 2 subunits, respectively. Moreover, mice lacking β 4 subunits do not express α 5‐containing receptors but still express a small number of α 3 β 2 receptors. Here, we investigated how synaptic transmission is affected in the SCG of α 5 β 4‐ KO and α 5 β 2‐ KO mice. Using an ex vivo SCG preparation, we stimulated the preganglionic cervical sympathetic trunk and measured compound action potentials ( CAP s) in the postganglionic internal carotid nerve. We found that CAP amplitude was unaffected in α 5 β 4‐ KO and α 5 β 2‐ KO ganglia, whereas the stimulation threshold for eliciting CAP s was significantly higher in α 5 β 4‐ KO ganglia. Moreover, intracellular recordings in SCG neurons revealed no difference in EPSP amplitude. We also found that the ganglionic blocking agent hexamethonium was the most potent in α 5 β 4‐ KO ganglia ( IC 50 : 22.1 μ mol/L), followed by α 5 β 2‐ KO ( IC 50 : 126.7 μ mol/L) and WT ganglia ( IC 50 : 389.2 μ mol/L). Based on these data, we estimated an IC 50 of 568.6 μ mol/L for a receptor population consisting solely of α 3 β 4 α 5 receptors; and we estimated that α 3 β 4 α 5 receptors comprise 72% of nAChR s expressed in the mouse SCG . Similarly, by measuring the effects of hexamethonium on AC h‐induced currents in cultured SCG neurons, we found that α 3 β ...

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“…The channel kinetics of nAChRs made up of α5, α3, and (32 nAChR subunits are slightly different from those of α3β2 nAChRs (488, 491). More dramatic changes in nAChR channel kinetics are observed when the α5 nAChR subunit incorporates into receptors with the α3 and β4 nAChR subunits; the burst duration of α3α5β2 nAChR channels is almost threefold longer than that of α3β4 nAChRs (488, 491). Notably, the α3β4 nAChR is already very different in function from α3β2 receptors.…”

Section: Nicotinic Receptor Subunit Structure and Diversity And Rmentioning

confidence: 90%

Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function

Albuquerque¹,

Pereira²,

Alkondon³

et al. 2009

Physiological Reviews

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The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of α-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer’s, Parkinson’s, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

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Hidden function of neuronal nicotinic acetylcholine receptor β2 subunits in ganglionic transmission: comparison to α5 and β4 subunits

Cited by 8 publications

References 86 publications

Activation and Inhibition of Mouse Muscle and Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes

Activation and Inhibition of Mouse Muscle and Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes

The role of the nAChR subunits α 5, β 2, and β 4 on synaptic transmission in the mouse superior cervical ganglion

Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function

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