Poulsen, Mette H3; Lucas, Simon4; Strømgaard, Kristian3; Kristensen, Anders S3
1 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet3 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet4 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet
The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels mediating the majority of fast excitatory synaptic transmission in the central nervous system (CNS). Polyamine toxins derived from spiders and wasps are use- and voltage-dependent channel blockers of Ca(2+)-permeable AMPARs. Recent studies have suggested that AMPAR block by polyamine toxins is modulated by auxiliary subunits from the class of transmembrane AMPAR regulatory proteins (TARPs), which may have implications for their use as tool compounds in native systems. We have explored the effect of the TARP γ-2 (also known as stargazin) on the inhibitory potency of three structurally different polyamine toxins at Ca(2+)-permeable homomeric GluA1 AMPARs expressed in oocytes. We find that polyamine toxin IC50 is differentially affected by presence of stargazin depending on the efficacy of the agonists used to activate GluA1. Co-assembly of GluA1 receptors with stargazin increases the potency of the polyamine toxins when activated by the weak partial agonist kainate, but has no effect in presence of full-agonist L-glutamate (Glu) and partial agonist (RS)-willardiine.
Neurochemical Research, 2014, Vol 39, Issue 10, p. 1906-1913