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Stargazin-related protein ?? is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth.

ABSTRACT: The role(s) of the newly discovered stargazin-like ?-subunit proteins remains unclear; although they are now widely accepted to be transmembrane AMPA receptor regulatory proteins (TARPs), rather than Ca²? channel subunits, it is possible that they have more general roles in trafficking within neurons. We previously found that ?? subunit is associated with vesicles when it is expressed in neurons and other cells. Here, we show that ?? is present mainly in retrogradely transported organelles in sympathetic neurons, where it colocalises with TrkA-YFP, and with the early endosome marker EEA1, suggesting that ?? localises to signalling endosomes. It was not found to colocalise with markers of the endoplasmic reticulum, mitochondria, lysosomes or late endosomes. Furthermore, knockdown of endogenous ?? by short hairpin RNA transfection into sympathetic neurons reduced neurite outgrowth. The same was true in the PC12 neuronal cell line, where neurite outgrowth was restored by overexpression of human ??. These findings open the possibility that ?? has an essential trafficking role in relation to neurite outgrowth as a component of endosomes involved in neurite extension and growth cone remodelling.

SUBMITTER: Waithe D

PROVIDER: S-EPMC3104035 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Stargazin-related protein γ₇ is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth.

Waithe Dominic D Ferron Laurent L Dolphin Annette C AC

Journal of cell science 20110524 Pt 12

The role(s) of the newly discovered stargazin-like γ-subunit proteins remains unclear; although they are now widely accepted to be transmembrane AMPA receptor regulatory proteins (TARPs), rather than Ca²⁺ channel subunits, it is possible that they have more general roles in trafficking within neurons. We previously found that γ₇ subunit is associated with vesicles when it is expressed in neurons and other cells. Here, we show that γ₇ is present mainly in retrogradely transported organelles in sy ...[more]

PMID: 21610096

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Project description:Peripheral sensory neurons in the dorsal root ganglia (DRG) are the initial transducers of sensory stimuli, including painful stimuli, from the periphery to central sensory and pain-processing centers. Small- to medium-diameter non-peptidergic neurons in the neonatal DRG express functional kainate receptors (KARs), one of three subfamilies of ionotropic glutamate receptors, as well as the putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2). Neto2 alters recombinant KAR function markedly but has yet to be confirmed as an auxiliary subunit that assembles with and alters the function of endogenous KARs. KARs in neonatal DRG require the GluK1 subunit as a necessary constituent, but it is unclear to what extent other KAR subunits contribute to the function and proposed roles of KARs in sensory ganglia, which include promotion of neurite outgrowth and modulation of glutamate release at the DRG-dorsal horn synapse. In addition, KARs containing the GluK1 subunit are implicated in modes of persistent but not acute pain signaling. We show here that the Neto2 protein is highly expressed in neonatal DRG and modifies KAR gating in DRG neurons in a developmentally regulated fashion in mice. Although normally at very low levels in adult DRG neurons, Neto2 protein expression can be upregulated via MEK/ERK signaling and after sciatic nerve crush and Neto2-/- neurons from adult mice have stunted neurite outgrowth. These data confirm that Neto2 is a bona fide KAR auxiliary subunit that is an important constituent of KARs early in sensory neuron development and suggest that Neto2 assembly is critical to KAR modulation of DRG neuron process outgrowth.SIGNIFICANCE STATEMENT Pain-transducing peripheral sensory neurons of the dorsal root ganglia (DRG) express kainate receptors (KARs), a subfamily of glutamate receptors that modulate neurite outgrowth and regulate glutamate release at the DRG-dorsal horn synapse. The putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2) is also expressed in DRG. We show here that it is a developmentally downregulated but dynamic component of KARs in these neurons, that it contributes to regulated neurite regrowth in adult neurons, and that it is increased in adult mice after nerve injury. Our data confirm Neto2 as a KAR auxiliary subunit and expand our knowledge of the molecular composition of KARs in nociceptive neurons, a key piece in understanding the mechanistic contribution of KAR signaling to pain-processing circuits.

Dataset Information

Stargazin-related protein ?? is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth.

Publications

Stargazin-related protein γ₇ is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth.

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