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Differential gene expression of neonatal and adult DRG neurons correlates with the differential sensitization of TRPV1 responses to nerve growth factor.

ABSTRACT: Cultures of neonatal and adult dorsal root ganglion (DRG) neurons are commonly used in in vitro models to study the ion channels and signaling events associated with peripheral sensation under various conditions. Differential responsiveness between neonatal and adult DRG neurons to physiological or pathological stimuli suggests potential differences in their gene expression profiles. We performed a microarray analysis of cultured adult and neonatal rat DRG neurons, which revealed distinct gene expression profiles especially of ion channels and signaling molecules at the genomic level. For example, Ca(2+)-stimulated adenylyl cyclase (AC) isoforms AC3 and AC8, PKC? and CaMKII?, the voltage-gated sodium channel ?1 and ?4, and potassium channels K(v)1.1, K(v)3.2, K(v)4.1, K(v)9.1, K(v)9.3, K(ir)3.4, K(ir)7.1, K(2P)1.1/TWIK-1 had significantly higher mRNA expression in adult rat DRG neurons, while Ca(2+)-inhibited AC5 and AC6, sodium channel Na(v)1.3 ? subunit, potassium channels K(ir)6.1, K(2P)10.1/TREK-2, calcium channel Ca(v)2.2 ?1 subunit, and its auxiliary subunits ?1 and ?3 were conversely down regulated in adult neurons. Importantly, higher adult neuron expression of ERK1/2, PI3K/P110?, but not of TRPV1 and TrkA, was found and confirmed by PCR and western blot. These latter findings are consistent with the key role of ERK and PI3K signaling in sensitization of TRPV1 by NGF and may explain our previously published observation that adult, but not neonatal, rat DRG neurons are sensitized by NGF.

SUBMITTER: Zhu W

PROVIDER: S-EPMC3156246 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Differential gene expression of neonatal and adult DRG neurons correlates with the differential sensitization of TRPV1 responses to nerve growth factor.

Zhu Weiguo W Oxford Gerry S GS

Neuroscience letters 20110629 3

Cultures of neonatal and adult dorsal root ganglion (DRG) neurons are commonly used in in vitro models to study the ion channels and signaling events associated with peripheral sensation under various conditions. Differential responsiveness between neonatal and adult DRG neurons to physiological or pathological stimuli suggests potential differences in their gene expression profiles. We performed a microarray analysis of cultured adult and neonatal rat DRG neurons, which revealed distinct gene e ...[more]

PMID: 21741445

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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

Differential gene expression of neonatal and adult DRG neurons correlates with the differential sensitization of TRPV1 responses to nerve growth factor.

Publications

Differential gene expression of neonatal and adult DRG neurons correlates with the differential sensitization of TRPV1 responses to nerve growth factor.

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