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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.

Received for publication February 29, 2008.

Accepted for publication March 31, 2008.

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

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