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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 α7 nAChR (α7) and α4/β2 nAChR (α4β2) displayed distinct patterns of expression, with α7 targeted preferentially to the somatodendritic compartments, whereas α4β2 was localized to both axonal and dendritic domains. When fused to CD4 or IL2RA (interleukin 2 receptor α subunit) proteins, which are normally distributed ubiquitously, the M3-M4 intracellular loop from the α7 subunit promoted dendritic expression, whereas the homologous M3-M4 loop from the α4 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 α4 loop and a 48-residue dileucine and tyrosine motif (YXXØ) containing a dendritic targeting sequence from the α7 loop. These results provide valuable information in understanding diverse roles of neuronal nAChRs in mediating and modulating synaptic transmission, synaptic plasticity, and nicotine addiction. [ABSTRACT FROM AUTHOR]