Laura Moreno Wasiliewski (left) and Andreas Reiner are studying how nerve cells communicate.
Photo Credit: © RUB, Marquard
Scientific Frontline: Extended "At a Glance" Summary: GluK2/GluK5 Kainate Receptor Heteromer
The Core Concept: The GluK2/GluK5 kainate receptor heteromer is a specialized ionotropic glutamate receptor complex in the brain, composed of two GluK2 and two GluK5 subunits, that functions as a glutamate-activated ion channel to transmit excitatory neuronal signals.
Key Distinction/Mechanism: Unlike other kainate receptors, ligand binding exclusively at the two structurally less-favorably positioned GluK5 subunits forces adjacent GluK2 subunits to move, activating a persistently open channel without triggering the extensive structural restructuring required for receptor desensitization (inactivation). Additionally, a unique structural interaction between opposing GluK5 subunits results in an unusually slow deactivation process that is nearly ten times slower than related receptor complexes.
Major Frameworks/Components:
- Ionotropic Glutamate Receptors (iGluRs): Transmembrane neuronal receptor proteins consisting of four subunits that form a shared ion channel pore, with each subunit possessing an independent glutamate binding site.
- Partial Occupancy Activation: Ligand binding (such as with the agonist 5-iodowillardiine) at only the two GluK5 subunits is functionally sufficient to elicit receptor activation and produce long-lasting, non-desensitizing currents.
- Subunit Interaction Dynamics: A distinct structural interaction specifically between opposing GluK5 subunits dictates the complex's functional properties, directly driving its unusually slow deactivation rate.
Branch of Science: Cellular Neurobiology, Structural Biology, Biochemistry, and Biophysics.
Future Application: Because the GluK2/GluK5 complex is the most common kainate receptor in the human brain, identifying its unique subunit interactions and functional partially-occupied states provides a foundation for developing highly specific, tailored neuro-therapeutics and pharmacological drugs.
Why It Matters: Elucidating the specialized, non-desensitizing gating mechanism of this receptor complex provides critical insight into the modulation of neuronal synapses, expanding current scientific understanding of excitatory neurotransmission and signaling dynamics in the central nervous system.
Nerve cells in the brain use chemical messengers for communication. The signals are interpreted by diverse sets of receptor proteins. A new study focusing on a specific receptor complex provides some surprising insights.
To transmit excitatory signals, nerve cells mostly use glutamate as a neurotransmitter. To detect these transmitter signals, the cells rely on a wide repertoire of receptors with different signaling properties. Researchers at the Chair of Cellular Neurobiology, led by Professor Andreas Reiner at Ruhr University Bochum, Germany, together with their collaborators in New York (Department of Biochemistry and Biophysics, Weill Cornell Medicine), investigated the function of a specific glutamate receptor complex and made some surprising observations. The findings were reported in the journal Nature Communications.
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 the 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,” Moreno Wasielewski explained, “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,” Reiner summarized. 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 that is responsible for the subsequent inactivation (desensitization) of the receptors. The latter is only observed when all four subunits are occupied.
The structures also revealed another surprising detail: a close interaction between the opposing GluK5 subunits was observed, which is a unique feature not 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,” Moreno Wasielewski said, summarizing 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 also make the receptor an interesting target for therapeutic purposes, especially since it appears to be the most common kainate receptor in the human brain. Because 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, nondesensitizing currents, which are rather unusual. “So far, it is also unclear to what 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,” Reiner explained. The obtained structural information could also enable the future development of specific drugs that are tailored to this particular receptor.
Published in journal: Nature Communications
Authors: Nandish K. Khanra, Alexa Strauss, Laura Moreno Wasielewski, Sophie Lenze, Joel Meyerson, Andreas Reiner, and Joshua Levitz
Source/Credit: Ruhr-Universität Bochum | Andreas Reiner and Meike Drießen
Edited by: Scientific Frontline
Reference Number: cbio060826_01