Pharmacology of Kainate Receptors

The pharmacological profile of the kainate receptors is very complex. The concentrations of glutamate or kainate required to activate the receptors assemblies varies across brain regions. For instance, the EC50 for glutamate in hippocampal neurons is over 300 μM but under 60 μM in dorsal root ganglion neurons, reflecting differences in the subunits expressed in these two neuronal populations. GluK1-3 subunits have an approximaltely x10-fold lower affinity for kainate than the GluK4,5 subunits. The affinity of any compound is thus dependent on the precise makeup of the individual receptor complex.

A major difficulty in the study of the functions of kainate receptors has been the inability to distinguish between individual subunits, and indeed between kainate and AMPA receptors, with pharmacological agents. Developments over the last few years have led to the introduction of new compounds that show a good degree of selectivity, particularly for GluK1. For instance ATPA, is a kainate receptor agonist that is selective for GluK1 and GluK1-containing receptor complexes. It is essentially inactive at GluK2 subunits and is poorly active at GluK3 subunits. LY382884 is a GluK1 selective antagonist that has been now used extensively in the study of kainate receptor function.

More recently, a series of willardiine derivatives that show selectivity for the GluK1 subunit of the kainate receptor complex have been developed by Prof David Jane. UBP296 (and its (S) enantiomer UBP302) has a greater selectivity and higher affinity for GluK1-containing receptors than LY382884, while UBP301 is a broad spectrum, high affinity kainate receptor antagonist (More et al 2004). Compounds with higher affinity still for GluK1 have since been developed, eg UBP304 (Dolman et al 2006). The highest affinity and most selective GluK1 receptor antagonist is currently ACET (also developed by David Jane; Dolman et al 2007) with a KB of approximately 5-7 nM for GluK1 containing receptors. This compound is now being used extensively to investigate kainate receptor function.

Agonists

CompoundATPAKainic AcidAMPA
Structure Chemical structure of ATPA Chemical structure of kainaic acid Chemical structure of AMPA
GluK1 EC50=0.33±0.05μM EC50=4.9±0.4μM EC50=208±42μM  
GluK2 NA EC50=1.1±0.1μM NA
GluK3 -    
GluK1/2 EC50=0.80 ± 0.07 EC50=7.4±1.1μM EC50=154±19μM
GluK1/5 EC50=0.38 ± 0.04 EC50=1.5±0.1μM EC50=123±5μM
GluK2/5 EC50=106 ± 16 EC50=0.6±0.1μM EC50=137±9μM
Refs Alt at al, 2004 Alt at al, 2004 Alt at al, 2004

Antagonists

CompoundACETUBP310UBP304UBP296LY382884NBQX
Structure Chemical structure of ACET Chemical structure of UBP310 Chemical sttructure of UBP304 Chemical structure of UBP296 Chemical structure of LY382884 Chemical structure of NBQX
GluK1 Kb=7±1nM Kb=10±1nM Kb=120±30nM Kb=0.6±0.1μM IC50=2±1μM IC50=25±4μM
GluK2 NA NA NA NA NA IC50=21±6μM
GluK3 EC50=92±9 EC50=23±2nM Kb=111±38nM Kb=374±122μM NA Kb=18±8μM
GluK1/2     Kb=120±10nM Kb=0.8±0.1μM  IC50=4±1μM IC50=18±8μM
GluK1/5 Kb=5±1nM Kb=8±2nM Kb=180±20nM Kb=1.0±0.4μM IC50=4±1μM IC50=26±7μM
GluK2/5 NA NA NA NA NA IC50=87±90μM
Refs Dolman et al, 2007 Dolman et al, 2007 Dolman et al 2006 Dolman et al, 2005 Alt at al, 2004 Alt at al, 2004
Perrais et al, 2009 Perrais et al, 2009 Dolman et al, 2005