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The Journal of Neuroscience, September 20, 2006, 26(38):9780-9793; doi:10.1523/JNEUROSCI.0840-06.2006

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Cellular/Molecular
Identification of Sequence Motifs That Target Neuronal Nicotinic Receptors to Dendrites and Axons

Jian Xu, Yongling Zhu, and Stephen F. Heinemann

Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037

Correspondence should be addressed to Dr. Stephen F. Heinemann, Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: heinemann{at}salk.edu

Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a family of ligand-gated ion channels that play important roles in central and peripheral nervous systems. The subcellular distribution of neuronal nAChRs has important implications for function and is not well understood. Here, we analyzed the targeting of two major types of neuronal nAChRs by expressing epitope-tagged subunits in cultured hippocampal neurons. Surprisingly, the 7 nAChR (7) and 4/2 nAChR (42) displayed distinct patterns of expression, with 7 targeted preferentially to the somatodendritic compartments, whereas 42 was localized to both axonal and dendritic domains. When fused to CD4 or IL2RA (interleukin 2 receptor subunit) proteins, which are normally distributed ubiquitously, the M3–M4 intracellular loop from the 7 subunit promoted dendritic expression, whereas the homologous M3–M4 loop from the 4 subunit led to surface axonal expression. Systemic screening and alanine substitution further identified a 25-residue leucine motif ([DE]XXXL[LI]) containing an axonal targeting sequence within the 4 loop and a 48-residue dileucine and tyrosine motif (YXXØ) containing a dendritic targeting sequence from the 7 loop. These results provide valuable information in understanding diverse roles of neuronal nAChRs in mediating and modulating synaptic transmission, synaptic plasticity, and nicotine addiction.

Key words: acetylcholine; receptor; dendrite; axon; synapse; nicotine

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Received Feb. 23, 2006; revised Aug. 8, 2006; accepted Aug. 8, 2006.

Correspondence should be addressed to Dr. Stephen F. Heinemann, Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: heinemann{at}salk.edu

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