Modulation of neurite outgrowth by activation of calcium‐permeable kainate receptors expressed by rat nociceptive‐like dorsal root ganglion neurons

Abstract

Neurite outgrowth is a fundamental step in establishing proper neuronal connections in the developing central nervous system. Dynamic control of outgrowth has been attributed to changes in growth cone Ca2+ levels in response to extracellular cues. Here we have investigated a possible role for Ca2+ permeable kainate (KA) receptors in regulating neurite outgrowth of nociceptive-like dorsal root ganglion (DRG) neurons. To identify KA receptor subunits likely to be involved, we used quantitative RT-PCR on acutely dissociated DRG and dorsal horn neurons. DRG neurons expressed more GluK1, particularly the GluK1b spice variant, than dorsal horn neurons. Conversely, dorsal horn neurons expressed more GluK2, particularly GluK2a, than DRG neurons. Further, an RNA editing assay indicated that the majority of GluK1 and GluK2 mRNA transcripts in DRG were unedited. Imaging Ca2+ transients following application of a KA receptor agonist to DRG and dorsal horn co-cultures revealed increases in intracellular Ca2+ in the growth cones of DRG neurons. In the majority of cases, this increase in Ca2+ was partly or completely blocked by Joro spider toxin (JSTX), an antagonist for Ca2+-permeable AMPA and KA receptors. Treatment of DRG/dorsal horn co-cultures with KA for 18 hours suppressed neurite outgrowth while application of the rapidly desensitizing KA receptor agonist SYM 2081, the competitive AMPA/KA receptor antagonist, CNQX, and JSTX or philanthotoxin enhanced neurite outgrowth and prevented KA effects on neurite outgrowth. Thus, Ca2+ entry through KA receptors at the growth cone of DRG neurons may be an important regulator of neurite outgrowth.

Possible Involvement of TLRs and Hemichannels in Stress-Induced CNS Dysfunction via Mastocytes, and Glia Activation

“…Additionally, in an animal model of schizophrenia, the stimulation of pregnant mothers with poly (I:C) results in reduced neuronal arborization of the offspring, which is correlated with a status of higher activation [213]. Interestingly, Cx HCs participate in neurite outgrowth [214] and release of ATP and glutamate [125], which also affect neuronal arborization [214, 215]. …”

RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury

“…ADAR2 expression and self-editing are induced in the injured DRG ADAR1 and -2 are known to be ubiquitously expressed in many tissues (6), including DRGs (19). On the other hand, ADAR3 is primarily located within the CNS (20).…”

Role of Presynaptic Glutamate Receptors in Pain Transmission at the Spinal Cord Level

“…Due to the developmentally-regulated RNA editing of the GluK1 subunit, DRG neurons from late embryonic and newborn rats are predominantly Ca 2+ - permeable but then become fully Ca 2+ - impermeable later in the first postnatal week. Calcium-permeable KARs on C-fiber growth cones could function as a signal for growing C fibers to stop in superficial DH and form synapses [24]. …”