Composed of different subunits
The structure of ionotropic glutamate receptors (iGluRs), which function as glutamate-activated ion channels in the membrane of neurons, has been known for many years. All iGluRs consist of four subunits that form a shared ion channel pore. Each subunit has a glutamate binding site. However, it remains largely unknown how glutamate binding affects individual subunits and how the subunits act together to cause opening and closing of their common pore. The research team investigated this mechanism for a special glutamate receptor complex, the so-called GluK2/GluK5 kainate receptor heteromer, which consists of two GluK2 and two GluK5 subunits.
One initial observation was that ligand binding at just the two GluK5 subunits is sufficient to cause receptor activation. Using fast patch-clamp measurements, Laura Moreno Wasielewski, one of the study’s first authors, was able to show that 5-iodowillardiine, an agonist that only binds at the two GluK5 subunits, puts the receptors into a permanently open state. “This is remarkable,” explains Laura Moreno Wasielewski, “since it had been assumed that only the GluK2 subunits may mediate activation, as they are more closely coupled to the ion channel pore.”
Structural biology studies show details
Cryo-electron microscopy studies conducted in the laboratory of Professor Joshua Levitz in the United States provided further insights into the gating mechanism of this receptor complex. The structures revealed that ligand binding at the GluK5 subunits causes a movement of the adjacent GluK2 subunits. “This was unexpected; however, it explains why the GluK5 subunits are able to open the channel pore, although they are structurally less favorably positioned to do so,” summarizes Andreas Reiner. The structures also confirmed that partial occupancy of the four subunits, which is sufficient to cause receptor activation, does not yet elicit the extensive restructuring which is responsible for the subsequent inactivation (desensitization) of the receptors. The latter is only observed when all four subunits are occupied.
The structures revealed also another surprising detail: A close interaction between the opposing GluK5 subunits was observed, which is a unique feature not being seen in other kainate or related AMPA receptor complexes. In accompanying patch-clamp measurements the researchers found that this interaction also plays an important functional role. “This interaction site appears to affect the unusually slow deactivation that is seen for GluK2/GluK5 receptors, which is around ten times slower than in other kainate receptors,” Laura Moreno Wasielewski summarizes her findings.
Function in the nervous system
How the receptor’s unusual properties contribute to neuronal function remains to be investigated. The GluK2/GluK5 receptor complex is known to primarily exert a modulatory influence on synapses. This may make the receptor also an interesting target for therapeutic purposes, especially since it appears to be the most common kainate receptor in the human brain. Since GluK2 and GluK5 subunits have different affinities for glutamate, the partially occupied states that were investigated in this study could be of actual physiological significance, as they could cause long-lasting, non-desensitizing currents, which are rather unusual. “So far, it is also unclear to which extent the slow deactivation of this receptor heteromer contributes to synaptic signals. The GluK5-GluK5 interactions we have identified here, now give us the possibility to address this experimentally,” explains Andreas Reiner. The obtained structural information could also enable the future development of specific drugs that are tailored to this particular receptor.
Nature Communications
Experimental study
Cells
Structures of Partially Occupied Hetero-Tetramers Provide Insight Into Kainate Receptor Activation and Desensitization
24-Apr-2026