A Proteomic Analysis Reveals the Interaction of GluK1 Ionotropic Kainate Receptor Subunits with Go Proteins

The natural partnership of GluK1 and Go proteins demonstrated in this study is very interesting. A mechanism by which the relationship between GluK1 and G proteins may explain NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in mossy fibre-CA3 synapses follows.

For AMPA receptors (AMPARs), phosphorylation of stargazin by NMDAR-dependent activation of CaMKII and protein kinase C (PKC) promotes stargazin-AMPAR complex synaptic trafficking (Opazo et al., 2010, Chen et al., 2000). This is a mechanism of synaptic plasticity by which NMDARs regulate the number of AMPARs at the synapse. Given that Neto1 and Neto2 both have a phosphorylation site analogous to that of stargazin, we can hypothesize that similar phosphorylation of Netos by CaMKII or PKC promotes Neto-dependent synaptic targeting of kainate receptors (KARs).

In mossy-fiber (MF)-CA3 synapses, GluK1-antagonists have elucidated GluK1's capacity for NMDAR-independent LTP (Bortolotto et al., 1999). Intriguingly, PKC is downstream of GluK1's metabotropic signaling (Rodriguez-Moreno and Lerma, 1998, Rodriguez-Moreno and Sihra, 2011, Frerking et al., 2001). Therefore, I hypothesize that PKC, activated by GluK1's metabotropic signalling, phosphorylates Netos to promote Neto-KAR synaptic targeting in manners similar to the increased synaptic targeting of stargazin-AMPARs induced when PKC phosphorylates TARPs. This provides a potential mechanism of activity-dependent upregulation of KAR-Neto synaptic expression, and explains GluK1's ability to induce activity-dependent LTP in mossy fibers independently of NMDARs. Moreover, this suggests an explanation for the metabotropic signalling of KARs: to activate this PKC cascade. PKC activation for AMPAR-mediated LTP, however, is dependent on NMDARs: This difference might underlie KARs' unique capacity among ionotropic glutamate receptors (GluRs) for NMDAR-independent LTP. Moreover, this supports the original idea that synapses exhibiting NMDAR-independent LTP rely on metabotropic-GluRs, not ionotropic-GluRs (Bashir et al., 1993): In the unique case of KARs, I suggest that NMDAR-independent MF-LTP relies on the metabotropic actions of an ionotropic receptor. This would explain why the broad-spectrum mGluR antagonist, LY341495, fails to block MF-LTP: because LY341495 does not antagonize KAR-metabotropic signalling (Fitzjohn et al., 1998). Accordingly, inhibiting PKC reduces KA EPSC amplitude (Collingridge and Isaac, 2003). The study claimed this was because inhibiting PKC prevents phosphorylation of GluK1: however, Netos ability to increase KA EPSCs in MF-CA3 synapses (Straub et al., 2011a), as well as the evidence presented above; suggests that inhibiting PKC might instead prevent phosphorylation of Netos and consequently reduce KAR-Neto synaptic expression to induce the decreased KA EPSC amplitude and diminished LTP.

References

BASHIR, Z. I., BORTOLOTTO, Z. A., DAVIES, C. H., BERRETTA, N., IRVING, A. J., SEAL, A. J., HENLEY, J. M., JANE, D. E., WATKINS, J. C., COLLINGRIDGE, G. L. 1993. Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors. Nature, 363, 347- 50.

BORTOLOTTO, Z. A., CLARKE, V. R., DELANY, C. M., PARRY, M. C., SMOLDERS, I., VIGNES, M., HO, K. H., MIU, P., BRINTON, B. T., FANTASKE, R., OGDEN, A., GATES, M., ORNSTEIN, P. L., LODGE, D., BLEAKMAN, D., COLLINGRIDGE, G. L. 1999. Kainate receptors are involved in synaptic plasticity. Nature, 402, 297-301.

CHEN, L., CHETKOVICH, D. M., PETRALIA, R. S., SWEENEY, N. T., KAWASAKI, Y., WENTHOLD, R. J., BREDT, D. S., NICOLL, R. A. 2000. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature, 408, 936-43.

COLLINGRIDGE, G. L. and ISAAC, J. T. 2003. Functional roles of protein interactions with AMPA and kainate receptors. Neurosci Res, 47, 3- 15.

FITZJOHN, S. M., BORTOLOTTO, Z. A., PALMER, M. J., DOHERTY, A. J., ORNSTEIN, P. L., SCHOEPP, D. D., KINGSTON, A. E., LODGE, D. and COLLINGRIDGE, G. L. 1998. The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity. Neuropharmacology, 37, 1445-58.

FRERKING, M., SCHMITZ, D., ZHOU, Q., JOHANSEN, J. and NICOLL, R. A. 2001. Kainate receptors depress excitatory synaptic transmission at CA3--CA1 synapses in the hippocampus via a direct presynaptic action. J Neurosci, 21, 2958-66.

OPAZO, P., LABRECQUE, S., TIGARET, C. M., FROUIN, A., WISEMAN, P. W., DE KONINCK, P. and CHOQUET, D. 2010. CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron, 67, 239-52.

RODRIGUEZ-MORENO, A. and LERMA, J. 1998. Kainate receptor modulation of GABA release involves a metabotropic function. Neuron, 20, 1211-8.

RODRIGUEZ-MORENO, A. and SIHRA, T. S. 2011. Metabotropic actions of kainate receptors in the control of glutamate release in the hippocampus. Adv Exp Med Biol, 717, 39-48.

STRAUB, C., HUNT, D. L., YAMASAKI, M., KIM, K. S., WATANABE, M., CASTILLO, P. E. and TOMITA, S. 2011a. Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1. Nat Neurosci, 14, 866-73.

Conflict of Interest:

None declared