http://www.sciencedirect.com/science/article/pii/S0924977X17300482
Abstract
Activation
of nicotinic acetylcholine receptors (nAChR) promotes the morphological
remodeling of cultured dopamine (DA) neurons, an effect requiring
functional DA D3 receptors (D3R). The aim of this study was to
investigate the mechanisms mediating D3R-nAChR cross-talk in the
modulation of DA neuron structural plasticity. By using bioluminescence
resonance energy transfer2 (BRET2) and proximity ligation assay (PLA), evidence for the existence of D3R-nAChR heteromers has been obtained. In particular, BRET2
showed that the D3R directly and specifically interacts with the β2
subunit of the nAChR. The D3R-nAChR complex was also identified in
cultured DA neurons and in mouse Substantia Nigra/Ventral Tegmental Area
by PLA. Cell permeable interfering peptides, containing highly charged
amino acid sequences from the third intracellular loop of D3R (TAT-D3R)
or the second intracellular loop of the β2 subunit (TAT-β2), were
developed. Both peptides, but not their scrambled counterparts,
significantly reduced the BRET2 signal generated by D3R-GFP2
and β2-Rluc. Similarly, the PLA signal was undetectable in DA neurons
exposed to the interfering peptides. Moreover, interfering peptides
abolished the neurotrophic effects of nicotine on DA neurons. Taken
together these data first demonstrate that a D3R-nAChR heteromer is
present in DA neurons and represents the functional unit mediating the
neurotrophic effects of nicotine.
Keywords
- Nicotine;
- Heteromerization;
- Plasticity;
- Dopamine;
- D3 Receptor;
- Nicotinic receptor
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