Kainate is a potent neurotoxin derived from a seaweed, Digenea simplex. The toxin has a high affinity for and lends its name to a distinct genetic family of ion channel receptors that are normally targeted by glutamate, the principal excitatory neurotransmitter in the brain.1 While broadly distributed, kainate receptors (KARs) are less abundant than the other glutamatergic receptor families, however they have long been implicated in the development and progression of epileptic seizures.2
Exposure to kainate induces symptoms and patterns of brain remodelling similar to that seen in temporal lobe epilepsy (TLE). While this has been used in the past to develop anti-epileptic drugs, until relatively recently none were targeted at the KARs themselves.3 Therapeutic options currently available for TLE and other forms of epilepsy, work by reducing the overall levels of neuronal excitability in the brain and often come with unwanted side-effects but progress in this compelling field of research has been hampered by a lack of highly selective agents with which to probe KAR function.
There are 5 subunits (GluK1-5) that can combine to form KARs. GluK1-3 may form functional channels on their own or in combination with the others, while GluK4-5 can only do so in combination with GluK1-3.1 Due to the highly similar genetic make-up of these subunits, most of what is known of them individually comes from studying each subunit in isolated cell expression systems.3 The most well studied KAR subunits are GluK1 and GluK2, which are highly expressed in and around the hippocampus, a key region of the brain involved in TLE. Under normal circumstances, GluK1 and 2 appear to play opposite roles to one another, with GluK2 present mostly on excitatory “principal” neurones in the hippocampal network, while GluK1 is more abundant on inhibitory “interneurons” that help regulate the activity of the former. In TLE, there is a major shift in the balance of signalling that results in GluK2 having a far greater influence with the result being a greater risk of epileptic patterns of activity.2
With this information, a first and obvious avenue for treatment might be to target the GluK2 receptors, however, in addition to the problems of selectivity, the picture is somewhat complicated by the presence of pre-synaptic GluK2 on inhibitory interneurons that actually enhance their inhibitory effects, inhibition of which would probably work against a blanket blockade of GluK2 receptors. Similarly, GluK1 is also present on principal cells and can reduce the regulatory effects mediated by cannabinoid receptors. 2
A way around these problems might be the development of allosteric modulators, drugs that positively or negatively alter receptor function, instead of just switching it off or on. By targeting specific GluK subunits in this manner, it may be possible to achieve better, targeted regulation of neuronal excitability. A development which may make this approach even more interesting is the report by Fisher that the different subunits in heteromeric KARs may independently influence the function of the whole channel without disrupting the normal functionality of the companion subunits.4 This is particularly intriguing from a drug development perspective as compounds developed on simpler, homomeric, receptors may still retain their expected functions at the more complex receptor mixes found on native neurones.
There may be much more to this tale yet.
- Traynelis, S.F., Wollmuth, L.P, McBain, C.J., Menniti, F.S., Vance, K.M., Ogden, K.K., Hansen, K.B., Yuan, H., Myers, S.J., Dingledine, R., and Sibley, D. (2010), Glutamate Receptor Ion Channels: Structure, Regulation, and Function. Pharmacological Reviews 62(3), 405-496
- Crépel, V. (2013), Kainate receptors in epilepsy. WIREs Membrane Transport and Signaling, 2: 75–83.
- Matute, C. (2011). Therapeutic Potential of Kainate Receptors. CNS Neuroscience & Therapeutics, 17(6), 661–669.
- Fisher, J. L. (2014). The neurotoxin domoate causes long-lasting inhibition of the kainate receptor GluK5 subunit. Neuropharmacology. 85, 9–17
Blog written by Iain Barrett