Abstract
The 5-HT2A serotonin receptor represents an important molecular target for atypical antipsychotic drugs and for most hallucinogens. In the mammalian cerebral cortex, 5-HT2A receptors are enriched in pyramidal neurons, within which 5-HT2A receptors are preferentially sorted to the apical dendrites. In primary cortical cultures, 5-HT2A receptors are sorted to dendrites and not found in the axons of pyramidal neurons. We identified a sorting motif that mediates the preferential targeting of 5-HT2A receptors to the dendrites of cortical pyramidal neurons in vitro. We constructed green fluorescent protein-tagged 5-HT2A receptors wherein potential sorting motifs were disrupted, and subsequently employed either the Semliki Forest virus or calcium phosphate for the transient expression of recombinant 5-HT2A receptors in cultured cortical pyramidal neurons. Using dual-labeling immunofluorescent confocal microscopy, we quantified the axonal and dendritic sorting patterns of endogenous and recombinant 5-HT2A receptors. We discovered that disruption of the PDZ-binding domain of the 5-HT2A receptor greatly attenuates the dendritic targeting of 5-HT2A receptors without inappropriately sorting 5-HT2A receptors to axons. The PDZ-binding domain is therefore a necessary signal for the preferential targeting of the 5-HT 2A receptor to the dendritic compartment of cultured cortical pyramidal neurons, the first such role ascribed to this protein-protein interaction motif of any G protein-coupled receptor.
Original language | English (US) |
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Pages (from-to) | 907-920 |
Number of pages | 14 |
Journal | Neuroscience |
Volume | 122 |
Issue number | 4 |
DOIs | |
State | Published - 2003 |
Externally published | Yes |
Keywords
- Axon
- Dendrite
- G protein-coupled receptor
- GPCR
- Neuronal polarity
- Polarized protein sorting
ASJC Scopus subject areas
- Neuroscience(all)