RIC‐3: a nicotinic acetylcholine receptor chaperone

Millar, Neil S.

doi:10.1038/sj.bjp.0707661

Cited by 116 publications

(139 citation statements)

References 69 publications

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“…Expression studies using heterologous systems have shown that nAChR assembly is a tightly regulated and ordered process, which requires appropriate subunit-subunit interactions and perhaps other proteins (chaperones) that can assist receptor assembly [52,53]. Vertebrate nAChR subunits may co-assemble in many possible combinations, and many more subtypes have been heterologously expressed than those identified in vivo.…”

Section: Nachr Subtype Assemblymentioning

confidence: 99%

Structural and functional diversity of native brain neuronal nicotinic receptors

Gotti

Clementi

Fornari

et al. 2009

Biochemical Pharmacology

424

430

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Although some of the neural circuits involved in the acute and chronic effects of nicotine have been identified, much less is known about which native nAChR subtypes are involved in specific physiological functions and pathophysiological conditions.We briefly review some recent findings concerning the structure and function of native nAChRs, focusing on the subtypes identified in the meso-striatal and habenulo-interpeduncular pathways, two systems involved in nicotine reinforcement and withdrawal. We also discuss recent findings concerning the effect of chronic nicotine on the expression of native subtypes.

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Section: Nachr Subtype Assemblymentioning

confidence: 99%

Structural and functional diversity of native brain neuronal nicotinic receptors

Gotti

Clementi

Fornari

et al. 2009

Biochemical Pharmacology

424

430

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“…RIC-3 is thought to act as a chaperone promoting AChR folding, assembly, or maturation (reviewed in ref. 15). unc-74 was identified in early screens for resistance to levamisole (4).…”

mentioning

confidence: 99%

Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor

Boulin

Gielen

Richmond

et al. 2008

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

178

311

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Levamisole-sensitive acetylcholine receptors (L-AChRs) are ligandgated ion channels that mediate excitatory neurotransmission at the neuromuscular junctions of nematodes. They constitute a major drug target for anthelminthic treatments because they can be activated by nematode-specific cholinergic agonists such as levamisole. Genetic screens conducted in Caenorhabditis elegans for resistance to levamisole toxicity identified genes that are indispensable for the biosynthesis of L-AChRs. These include 5 genes encoding distinct AChR subunits and 3 genes coding for ancillary proteins involved in assembly and trafficking of the receptors. Despite extensive analysis of L-AChRs in vivo, pharmacological and biophysical characterization of these receptors has been greatly hampered by the absence of a heterologous expression system. Using Xenopus laevis oocytes, we were able to reconstitute functional L-AChRs by coexpressing the 5 distinct receptor subunits and the 3 ancillary proteins. Strikingly, this system recapitulates the genetic requirements for receptor expression in vivo because omission of any of these 8 genes dramatically impairs L-AChR expression. We demonstrate that 3 ␣-and 2 non-␣-subunits assemble into the same receptor. Pharmacological analysis reveals that the prototypical cholinergic agonist nicotine is unable to activate L-AChRs but rather acts as a potent allosteric inhibitor. These results emphasize the role of ancillary proteins for efficient expression of recombinant neurotransmitter receptors and open the way for in vitro screening of novel anthelminthic agents.anthelminthic drug ͉ recombinant receptor expression

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“…For example, RIC-3, a transmembrane protein which acts as a molecular chaperone, is required for efficient receptor folding, assembly, and functional expression of the α7 nAChR (Millar 2008). Similar chaperon proteins have not been described in the case of α9α10 receptors.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Expression of the α10 Nicotinic Acetylcholine Receptor Subunit Fails to Maintain Cholinergic Responses in Inner Hair Cells After the Onset of Hearing

Taranda

Ballestero

Hiel

et al. 2009

JARO

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Efferent inhibition of cochlear hair cells is mediated by α9α10 nicotinic cholinergic receptors (nAChRs) functionally coupled to calcium-activated, small conductance (SK2) potassium channels. Before the onset of hearing, efferent fibers transiently make functional cholinergic synapses with inner hair cells (IHCs). The retraction of these fibers after the onset of hearing correlates with the cessation of transcription of the Chrna10 (but not the Chrna9) gene in IHCs. To further analyze this developmental change, we generated a transgenic mice whose IHCs constitutively express α10 into adulthood by expressing the α10 cDNA under the control of the Pou4f3 gene promoter. In situ hybridization showed that the α10 mRNA is expressed in IHCs of 8-week-old transgenic mice, but not in wild-type mice. Moreover, this mRNA is translated into a functional protein, since IHCs from P8-P10 α10 transgenic mice backcrossed to a Chrna10 −/− background (whose IHCs have no cholinergic function) displayed normal synaptic and acetylcholine (ACh)-evoked currents in patch-clamp recordings. Thus, the α10 transgene restored nAChR function. However, in the α10 transgenic mice, no synaptic or ACh-evoked currents were observed in P16-18 IHCs, indicating developmental downregulation of functional nAChRs after the onset of hearing, as normally observed in wild-type mice. The lack of functional ACh currents correlated with the lack of SK2 currents. These results indicate that multiple features of the efferent postsynaptic complex to IHCs, in addition to the nAChR subunits, are down-regulated in synchrony after the onset of hearing, leading to lack of responses to ACh.

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RIC‐3: a nicotinic acetylcholine receptor chaperone

Cited by 116 publications

References 69 publications

Structural and functional diversity of native brain neuronal nicotinic receptors

Structural and functional diversity of native brain neuronal nicotinic receptors

Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor

Constitutive Expression of the α10 Nicotinic Acetylcholine Receptor Subunit Fails to Maintain Cholinergic Responses in Inner Hair Cells After the Onset of Hearing

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