QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.108.046789v1 74/1/132    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Kuryatov, A. Articles by Lindstrom, J. PubMed PubMed Citation Articles by Kuryatov, A. Articles by Lindstrom, J.

Roles of Accessory Subunits in 4β2^* Nicotinic Receptors

Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania

Accessory subunits in heteromeric nicotinic receptors (AChRs) do not take part in forming ACh binding sites. 5 and β3 subunits can function only as accessory subunits. We show that both 5 and β3 efficiently assemble in human 4β2^* AChRs expressed in permanently transfected human embryonic kidney (HEK) cell lines. Only (4β2)₂5, not (4β2)₂β3 AChRs, have been detected in brain. The 4β25 line expressed 40% more AChRs than the parent 4β2 line and was equally sensitive to up-regulation by nicotine. The 4β2β3 line expressed 25-fold more AChRs than the parental line and could not be further up-regulated by nicotine. Relative sensitivity to activation by ACh depends on the accessory subunit, β2 conferring the greatest sensitivity, 5 less, and β3 and 4 much less. Accessory subunits form binding sites for positive allosteric modulators, as illustrated by the observation that 5 conferred high sensitivity to galanthamine. In the presence of 5 or β3, stable, partially degraded, dead end intermediates accumulated within the cells. These may have the form 54β25. The efficiency with which 5 and β3 assemble with 4 and β2 and the necessity of avoiding formation of potentially toxic intermediates may explain why 5 and β3 seem to be transcribed at low levels in brain. Autosomal dominant nocturnal frontal lobe epilepsy can be caused by the 4 mutation S247F. This mutant did not produce functional AChRs unless cells were cotransfected with 5, β3, or 6 to replace 4 as accessory subunit.

Address correspondence to: Jon Lindstrom, Department of Neuroscience, University of Pennsylvania Medical School, 217 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104. E-mail: jslkk{at}mail.med.upenn.edu

This article has been cited by other articles:

				S. M. Kassam, P. M. Herman, N. M. Goodfellow, N. C. Alves, and E. K. Lambe Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors J. Neurosci., August 27, 2008; 28(35): 8756 - 8764. [Abstract] [Full Text] [PDF]