Motif controls nicotinic receptors

A transmembrane motif controls the endoplasmic reticulum release of nicotinic acetylcholine receptor subunits. | Tudor P Toma

The nicotinic acetylcholine receptor (AChR) is assembled on the cell surface from multiple subunits produced in the endoplasmic reticulum (ER), but how these mechanisms are controlled has been unclear. In September 9 Nature Neuroscience, Jun-Mei Wang and colleagues at the University of Pittsburgh School of Medicine, USA, show that a transmembrane motif performs the biosynthetic quality control during subunit assembly of functional AChR complexes (Nat Neurosci 2002, DOI:10.1038/nn918).

Wang et al. transfected COS cells with a number of different nicotinic receptor subunits and observed that a PL(Y/F)(F/Y)xxN motif conserved in the membrane domain of AChR acted to retain and degrade unassembled AChRs. Insertion of this motif into unrelated proteins normally transported to the surface resulted in ER retention. In addition, they showed that the signal is buried in AChR pentamers, but is exposed on unassembled subunits in the ER, where it promotes protein degradation.

Clinically, AChRs mediate nicotine addiction and are specifically reduced in Alzheimer's disease and schizophrenia. Consequently, understanding the mechanisms that control AChR surface trafficking may identify novel drug targets for these conditions.