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Nicotinic acetylcholine receptors regulate vestibular afferent gain and activation timing.

ABSTRACT: Little is known about the function of the cholinergic efferents innervating peripheral vestibular hair cells. We measured vestibular sensory evoked potentials (VsEPs) in ?9 knockout (KO) mice, ?10 KO mice, ?7 KO mice, ?9/10 and ?7/9 double KO mice, and wild-type (WT) controls. We also studied the morphology and ultrastructure of efferent terminals on vestibular hair cells in ?9, ?10, and ?9/10 KOs. Both type I and type ll vestibular hair cells express the ?9 and ?10 subunits. The efferent boutons on vestibular cells in ?9, ?10, and ?9/10 KOs appeared normal, but a quantitative analysis was not performed. Mean VsEP thresholds were significantly elevated in ?9 and ?9/10 KO animals. Some ?9 and ?9/10 KO animals, however, had normal or near-normal thresholds, whereas others were greatly affected. Despite individual variability in threshold responses, latencies were consistently shortened. The double ?7/9 KO resulted in decreased variance by normalizing waveforms and latencies. The phenotypes of the ?7 and ?10 single KOs were identical. Both ?7 and ?10 KO mice evidenced normal thresholds, decreased activation latencies, and larger amplitudes compared with WT mice. The data suggest a complex interaction of nicotinic acetylcholine receptors (nAChRs) in regulating vestibular afferent gain and activation timing. Although the ?9/10 heteromeric nAChR is an important component of vestibular efferent activity, other peripheral or central nAChRs involving the ?7 subunit or ?10 subunit and ?9 homomeric receptors are also important. J. Comp. Neurol. 525:1216-1233, 2017. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Morley BJ

PROVIDER: S-EPMC6677144 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Nicotinic acetylcholine receptors regulate vestibular afferent gain and activation timing.

Morley Barbara J BJ Lysakowski Anna A Vijayakumar Sarath S Menapace Deanna D Jones Timothy A TA

The Journal of comparative neurology 20161121 5

Little is known about the function of the cholinergic efferents innervating peripheral vestibular hair cells. We measured vestibular sensory evoked potentials (VsEPs) in α9 knockout (KO) mice, α10 KO mice, α7 KO mice, α9/10 and α7/9 double KO mice, and wild-type (WT) controls. We also studied the morphology and ultrastructure of efferent terminals on vestibular hair cells in α9, α10, and α9/10 KOs. Both type I and type ll vestibular hair cells express the α9 and α10 subunits. The efferent bouton ...[more]

PMID: 27718229

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Project description:The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ?300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by ?Y190) that behaves similarly at all sites and a coupled pair (led by ?W55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of ?(1) and one each of ?, ?, and either ? (fetal) or ? (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at ?? and either ?? or ?? subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C?O opening rate constant and C?O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly to reach a peak that corresponds to PO ?0.96.

Project description:Allelic variation in CHRNA3, the gene encoding the α3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for α3-containing (α3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. α3* nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that Chrna3tm1.1Hwrt hypomorphic mice, which express constitutively low levels of α3* nAChRs, self-administer greater quantities of nicotine (0.4 mg kg-1 per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down Chrna3 transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg-1 per infusion). Using whole-cell recordings, we found that the α3β4* nAChR-selective antagonist α-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the α3β2* nAChR-selective antagonist α-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of α-conotoxin AuIB (10 μm) but not α-conotoxin MII (10 μm) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that α3β4* nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how CHRNA3 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers.SIGNIFICANCE STATEMENT Allelic variation in CHRNA3, which encodes the α3 nicotinic acetylcholine receptor (nAChR) subunit gene, increases risk of tobacco dependence but underlying mechanisms are unclear. We report that Chrna3 hypomorphic mice consume greater quantities of nicotine than wild-type mice and that knock-down of Chrna3 gene transcripts in the habenula or interpeduncular nucleus (IPn) increases nicotine intake in rats. α-Conotoxin AuIB, a potent antagonist of the α3β4 nAChR subtype, reduced the stimulatory effects of nicotine on habenular neurons, and its infusion into the IPn increased nicotine intake in rats. These data suggest that α3β4 nAChRs in the habenula-IPn circuit regulate the motivational properties of nicotine.

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Nicotinic acetylcholine receptors regulate vestibular afferent gain and activation timing.

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Nicotinic acetylcholine receptors regulate vestibular afferent gain and activation timing.

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