Abstract| Volume 16, ISSUE 4, SUPPLEMENT , S61, April 2015

(342) Kainate receptor composition in primary sensory neurons

      Kainate receptors (KARs), one of three families of ionotropic glutamate receptors, are expressed throughout the peripheral and central nervous system, including in those pathways comprising the pain neuraxis. Both human and animal studies support a role for KARs, and in particular GluK1-containing receptors, in the mediation of aggravated pain rather than acute pain. KARs are expressed in dorsal root ganglion (DRG) neurons, as well as many locations throughout the pain neuraxis. Recently, the auxiliary subunits neuropilin and tolloid-like 1 (Neto1) and Neto2 were shown to profoundly modulate recombinant and endogenous KARs in receptor subunit- and Neto isoform-dependent fashions, and therefore could be important but poorly characterized constituents of KAR function in sensory pathways. We hypothesize that Neto proteins impact KAR functions in peripheral sensory neurons by functionally assembling with pore-forming subunits in DRG neurons. To test our hypothesis we recorded glutamate-evoked currents from DRG neurons isolated from wildtype and Neto-null mice. We find that KAR kinetics are altered in Neto2-null DRG neurons, suggesting functional assembly of Neto2 with native receptors in peripheral sensory neurons. Unlike neonatal neurons, adult DRG neurons express very little Neto2 upon acute dissociation suggesting a greater role for Neto2 in development than in the adult. Adult neurons do upregulate Neto2 over time in culture and we are pursuing the relevance this has to adult DRG function. Despite the demonstrated importance of GluK1 in formalin-induced spontaneous pain and hypersensitivity, we find these pain modalities to be unaffected by global deletion of Neto proteins and are investigating the role of Neto2 in other pain modalities. Elucidation of how Neto proteins shape KAR function in sensory signaling pathways is key for developing a clear mechanistic understanding of KARs’ contribution to sensory transmission and their potential utility as therapeutic targets. Supported by NINDS R01 NS071952 and the Julius Kahn Fellowship.