Abstract

Rat brain presynaptic 5-HT 3 serotonin receptors, members of the ligand-gated ion channel superfamily, induce changes in nerve terminal [Ca 2+] i in a manner distinct from that found for somatic 5-HT 3 receptors. Here, we assessed the role of postsynaptic target in regulating the nature of presynaptic receptor-induced responses, using the hybrid neuroblastoma cell line NG108-15 as a model neuronal system that expresses 5-HT 3 receptors. Using immunocytochemistry, 5-HT 3 receptors were found to be present on the presynaptic-like varicosities of differentiated NG108-15 cells, indicating that these receptors possess an inherent ability to localize to potential presynaptic sites. In the absence of postsynaptic target, 5-HT 3 receptors localized to the varicosities induce rapid but transient changes in [Ca 2+] i that were initiated by voltage-gated Ca 2+ channels, as assessed using Ca 2+ channel blockers, these properties being typical of those found for somatic 5-HT 3 receptors. In co-cultures containing rat myotubes, with which NG108-15 cells form functional cholinergic synapses, the 5-HT 3 receptor-induced changes in [Ca 2+] i in the axonal varicosities shifted over time (three to 10 days) to that found for brain nerve endings: sustained responses that were insensitive to blockade by antagonists of voltage-gated Ca 2+ channels. The effect of co-culturing myotubes with the NG108-15 cells was mimicked by conditioned media from myotube cultures. These results indicate that regulatory molecules from the target postsynaptic cell dictate the functional responses elicited by presynaptic 5-HT 3 receptors. Because the target-induced changes required several days before they were evident, we hypothesize that changes in protein expression, perhaps the consequence of altered gene regulation, underlie the changes in the responses to 5-HT 3 receptor activation in the axonal varicosities of this neuronal cell line.

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