GPRIN proteins and their effects on kainate receptor function

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The ionotropic glutamate receptors are ligand-gated channels of critical importance for neuronal communication in the central nervous system; mutations that impair receptor function cause neurological phenotypes that include severe neurodevelopmental disturbances. These receptors have been grouped into three categories and named according to their pharmacological agonists: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainic acid (KA). While AMPA and NMDA receptors mediate most of the fast excitatory postsynaptic currents in the brain, the KA receptor (KAR) contribution to postsynaptic excitability is localised to discrete synapses, and these ionotropic glutamate receptors seem to serve more diverse functions than the other two types. Interestingly, unlike NMDA and AMPA receptor functions, many KAR functions are mediated by activation of heterotrimeric G proteins, in a non-canonical, metabotropic way, even though KARs do not belong to the G protein-coupled receptor family (GPCRs). We are interested in the identification and functional characterisation of KAR-interacting proteins, and we have recently identified a KAR-interacting protein known as G protein-regulated inducer of neurite outgrowth 1 (GPRIN1). We hypothesise that GPRIN1 modulates specific characteristics of KAR currents, such as their slow kinetics. Moreover, GPRIN1 may be involved in the KAR modulation of neuronal development and function as a partner in a complex with heterotrimeric G proteins. To elucidate the role of the association between GPRINs and KARs, we will work in a programme composed of two sub-projects. First, we will dissect the nature of the interaction between KARs and members of the GPRIN family and examine the functional consequences of this interaction using biochemical and cell-based assays. Next, we will investigate the physiological conditions that influence the functional association of these two proteins and also explore the relevance of functional GPRIN for endogenous KAR function.