Differential agonist sensitivity of glycine receptor α 2 subunit splice variants

The glycine receptor (GlyR) α 2A and α 2B splice variants differ by a dual, adjacent amino acid substitution from α 2A V58,T59 to α 2B I58,A59 in the N‐terminal extracellular domain. Comparing the effects of the GlyR agonists, glycine, β ‐alanine and taurine, on the GlyR α 2 isoforms, revealed a significant increase in potency for all three agonists at the α 2B variant. The sensitivities of the splice variants to the competitive antagonist, strychnine, and to the biphasic modulator Zn 2+ , were comparable. In contrast, the allosteric inhibitor picrotoxin was more potent on GlyR α 2A compared to GlyR α 2B receptors. Coexpression of α 2A or α 2B subunits with the GlyR β subunit revealed that the higher agonist potencies observed with the α 2B homomer were retained for the α 2B β heteromer. The identical sensitivity to strychnine combined with a reduction in the maximum current induced by the partial agonist taurine at the GlyR α 2A homomer, suggested that the changed sensitivity to agonists is in accordance with a modulation of agonist efficacy rather than agonist affinity. An effect on agonist efficacy was also supported by using a structural model of the GlyR, localising the region of splice variation to the proposed docking region between GlyR loop 2 and the TM2‐3 loop, an area associated with channel activation. The existence of a spasmodic mouse phenotype linked to a GlyR α 1 A52S mutation, the equivalent position to the source of the α 2 splice variation, raises the possibility that the GlyR α 2 splice variants may be responsible for distinct roles in neuronal function.British Journal of Pharmacology (2004) 143 , 19–26. doi: 10.1038/sj.bjp.0705875