These studies explored whether the localization and differential trafficking itineraries of G protein-coupled receptors in polarized renal epithelial cells might predict their localization in neurons, as suggested previously. The A1 adenosine receptor is preferentially localized apically, whereas the three alpha 2-adrenergic receptor (alpha 2 AR) subtypes are localized on the lateral subdomain of Madin-Darby canine kidney cells. The alpha 2A AR and alpha 2C AR subtypes achieve this localization by direct targeting; alpha 2B AR is randomly delivered but preferentially retained basolaterally. Despite their differing itineraries in renal epithelial cells, all three epitope-tagged alpha 2-adrenergic receptor subtypes were found in neuronal cell bodies and along the entire length of the neuronal processes following transfection into long term primary cultures of mouse embryonic spinal cord neurons. In a small fraction of neuronal cells, expression of A1 adenosine receptor was limited to a short segment of their processes, otherwise it too was distributed in the soma and neuronal processes. A mutant alpha 2A AR that exhibits an accelerated turnover on the surface of epithelial cells nonetheless has a localization pattern indistinguishable from the wild-type alpha 2A AR in spinal cord neurons. Thus, unlike examples for GPI-anchored apical proteins that distribute along axons or single transmembrane-spanning basolateral proteins that localize to the soma of neurons, similar predictions do not appear to apply for polytopic G protein-coupled receptors.