Presynaptic kainate receptor-mediated bidirectional modulatory actions: Mechanisms

• KARs have an autoreceptor role in modulating glutamate release.
• KAR-mediated depression of glutamate release involves iono- and metabotropic actions.
• KAR-mediated facilitation of glutamate release is independent of G-proteins.
• KAR-mediated facilitation of glutamate release involves calcium signaling.
• KAR-mediated facilitation of glutamate release involves calcium–calmodulin.

Kainate receptors (KARs) are members of the glutamate receptor family, which also includes two other ionotropic subtypes, i.e. NMDA- and AMPA-type receptors, and types I, II and III metabotropic glutamate receptors. KARs mediate synaptic transmission postynaptically through their ionotropic capacity, while presynaptically, they modulate the release of both GABA and glutamate through operationally diverse modus operandi. At hippocampal mossy fiber (MF)-CA3 synapses, KARs have a biphasic effect on glutamate release, such that, depending on the extent of their activation, a facilitation or depression of glutamate release can be observed. This modulation is posited to contribute to important roles of KARs in short- and long-term plasticity. Elucidation of the modes of action of KARs in their depression and facilitation of glutamate release is beginning to gather impetus. Here we will focus on the cellular mechanisms involved in the modulation of glutamate release by presynaptic KAR activation at MF-CA3 synapses, a field that has seen significant progress in recent years.