A New Mechanism of Receptor Targeting by Interaction between Two Classes of Ligand-Gated Ion Channels
J. Neurosci.. 2016-02-03; 36(5): 1456-1470
DOI: 10.1523/JNEUROSCI.2390-15.2016
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1. J Neurosci. 2016 Feb 3;36(5):1456-70. doi: 10.1523/JNEUROSCI.2390-15.2016.
A New Mechanism of Receptor Targeting by Interaction between Two Classes of
Ligand-Gated Ion Channels.
Emerit MB(1), Baranowski C(2), Diaz J(2), Martinez A(3), Areias J(2), Alterio
J(2), Masson J(2), Boué-Grabot E(3), Darmon M(2).
Author information:
(1)Centre de Psychiatrie et Neurosciences, INSERM UMR 894, 75013 Paris, France,
Université Paris V, 75006 Paris, France, .
(2)Centre de Psychiatrie et Neurosciences, INSERM UMR 894, 75013 Paris, France,
Université Paris V, 75006 Paris, France.
(3)Institut des Maladies Neurodégénératives, CNRS UMR 5293, 33076 Bordeaux,
France, and Université de Bordeaux, 33076 Bordeaux, France.
The 5-HT3 receptors are serotonin-gated ion channels that physically couple with
purinergic P2X2 receptors to trigger a functional cross-inhibition leading to
reciprocal channel occlusion. Although this functional receptor-receptor coupling
seems to serve a modulatory role on both channels, this might not be its main
physiological purpose. Using primary cultures of rat hippocampal neurons as a
quantitative model of polarized targeting, we show here a novel function for this
interaction. In this model, 5-HT3A receptors did not exhibit by themselves the
capability of distal targeting in dendrites and axons but required the presence
of P2X2R for their proper subcellular localization. 5-HT3AR distal targeting
occurred with a delayed time course and exhibited a neuron phenotype dependency.
In the subpopulation of neurons expressing endogenous P2X2R, 5-HT3AR distal
neuritic localization correlated with P2X2R expression and could be selectively
inhibited by P2X2R RNA interference. Cotransfection of both receptors revealed a
specific colocalization, cotrafficking in common surface clusters, and the axonal
rerouting of 5-HT3AR. The physical association between the two receptors was
dependent on the second intracellular loop of the 5-HT3A subunit, but not on the
P2X2R C-terminal tail that triggers the functional cross-inhibition with the
5-HT3AR. Together, these data establish that 5-HT3AR distal targeting in axons
and dendrites primarily depends on P2X2R expression. Because several P2XR have
now been shown to functionally interact with several other members of the 4-TMD
family of receptor channels, we propose to reconsider the real functional role
for this receptor family, as trafficking partner proteins dynamically involved in
other receptors targeting.SIGNIFICANCE STATEMENT: So far, receptor targeting
mechanisms were found to involve intracellular partner proteins or supramolecular
complexes that couple receptors to cytoskeletal elements and recruit them into
cargo vesicles. In this paper, we describe a new trafficking mechanism for the
neuronal serotonin 5-HT3A ionotropic channel receptor, in which the role of
routing partner is endowed by a functionally interacting purinergic receptor: the
P2X2 receptor. This work not only unveils the mechanism by which 5-HT3 receptors
can reach their axonal localization required for the control of neurotransmitter
release, but also suggests that, in addition to their modulatory role, the family
of P2X receptors could have a previously undescribed functional role of
trafficking partner proteins dynamically involved in the targeting of other
receptors.
Copyright © 2016 the authors 0270-6474/16/361456-15$15.00/0.
DOI: 10.1523/JNEUROSCI.2390-15.2016
PMID: 26843630 [Indexed for MEDLINE]