Extrinsic factors regulate partial agonist efficacy of strychnine-sensitive glycine receptors

BACKGROUND: Strychnine-sensitive glycine receptors in many adult forebrain regions consist of alpha(2 )+ beta heteromeric channels. This subunit composition is distinct from the alpha(1 )+ beta channels found throughout the adult spinal cord. Unfortunately, the pharmacology of forebrain alpha(2)beta receptors are poorly defined compared to 'neonatal' alpha(2 )homomeric channels or 'spinal' alpha(1)beta heteromers. In addition, the pharmacologic properties of native alpha(2)beta glycine receptors have been generally distinct from receptors produced by heterologous expression. To identify subtype-specific pharmacologic tools for the forebrain alpha(2)beta receptors, it is important to identify a heterologous expression system that closely resembles these native glycine-gated chloride channels. RESULTS: While exploring pharmacological properties of alpha(2)beta glycine receptors compared to alpha(2)-homomers, we found that distinct heterologous expression systems appeared to differentially influence partial agonist pharmacology. The β-amino acid taurine possessed 30–50% efficacy for alpha(2)-containing receptor isoforms when expressed in HEK 293 cells. However, taurine efficacy was dramatically reduced in L-cell fibroblasts. Similar results were obtained for β-alanine. The efficacy of these partial agonists was also strongly reduced by the beta subunit. There were no significant differences in apparent strychnine affinity values calculated from concentration-response data between expression systems or subunit combinations. Nor did relative levels of expression correlate with partial agonist efficacy when compared within or between several different expression systems. Finally, disruption of the tubulin cytoskeleton reduced the efficacy of partial agonists in a subunit-dependent, but system-independent, fashion. CONCLUSIONS: Our results suggest that different heterologous expression systems can dramatically influence the agonist pharmacology of strychnine-sensitive glycine receptors. In the systems examine here, these effects are independent of both absolute expression level and any system-related alterations in the agonist binding site. We conclude that complex interactions between receptor composition and extrinsic factors may play a significant role in determining strychnine-sensitive glycine receptor partial agonist pharmacology.