RIC-3 differentially modulates α4ß2 and α7 nicotinic receptor assembly, expression, and nicotine-induced receptor upregulation.
BMC Neurosci
; 14: 47, 2013 Apr 15.
Article
em En
| MEDLINE
| ID: mdl-23586521
ABSTRACT
BACKGROUND:
Recent work has shown that the chaperone resistant to inhibitors of acetylcholinesterase (RIC-3) is critical for the folding, maturation and functional expression of a variety of neuronal nicotinic acetylcholine receptors. α7 nicotinic receptors can only assemble and functionally express in select lines of cells, provided that RIC-3 is present. In contrast, α4ß2 nicotinic receptors can functionally express in many cell lines even without the presence of RIC-3. Depending on the cell line, RIC-3 has differential effects on α4ß2 receptor function - enhancement in mammalian cells but inhibition in Xenopus oocytes. Other differences between the two receptor types include nicotine-induced upregulation. When expressed in cell lines, α4ß2 receptors readily and robustly upregulate with chronic nicotine exposure. However, α7 nicotinic receptors appear more resistant and require higher concentrations of nicotine to induce upregulation. Could the coexpression of RIC-3 modulate the extent of nicotine-induced upregulation not only for α7 receptors but also α4ß2 receptors? We compared and contrasted the effects of RIC-3 on assembly, trafficking, protein expression and nicotine-induced upregulation on both α7 and α4ß2 receptors using fluorescent protein tagged nicotinic receptors and Förster resonance energy transfer (FRET) microscopy imaging.RESULTS:
RIC-3 increases assembly and cell surface trafficking of α7 receptors but does not alter α7 protein expression in transfected HEK293T cells. In contrast, RIC-3 does not affect assembly of α4ß2 receptors but increases α4 and ß2 subunit protein expression. Acute nicotine (30 min exposure) was sufficient to upregulate FRET between α4 and ß2 subunits. Surprisingly, when RIC-3 was coexpressed with α4ß2 receptors nicotine-induced upregulation was prevented. α7 receptors did not upregulate with acute nicotine in the presence or absence of RIC-3.CONCLUSIONS:
These results provide interesting novel data that RIC-3 differentially regulates assembly and expression of different nicotinic receptor subunits. These results also show that nicotine-mediated upregulation of α4ß2 receptors can be dynamically regulated by the presence of the chaperone, RIC-3. This could explain a novel mechanism why high affinity α4ß2 receptors are upregulated in specific neuronal subtypes in the brain and not others.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Nicotínicos
/
Agonistas Nicotínicos
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Peptídeos e Proteínas de Sinalização Intracelular
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Receptor Nicotínico de Acetilcolina alfa7
/
Nicotina
Limite:
Humans
Idioma:
En
Revista:
BMC Neurosci
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2013
Tipo de documento:
Article