Overview
- Trattnig, S.M. et. al. (2012) J. Biol. Chem. 287, 25241.
Alomone Labs PU02 blocks 5-HT3A receptors expressed in HEK 293T cells.5-HT3A receptor currents were elicited by 10 µM 5-HT, delivered every 3 minutes. PU02 (#P-165) was applied 30 seconds before stimulation at 0.1, 1 and 10 µM as indicated and inhibited the 5-HT induced current in a dose dependent and reversible manner.
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter synthesized from the amino acid Tryptophan by the enzyme tryptophan-decarboxylase. The 5-HT3 channel is a ligand gated ion channel receptor of the cys-loop channel family. It is a pentamer with five subunits surrounding a central channel1.
PU02 is a synthetic, potent and selective negative allosteric modulator of the 5-HT3 receptor. PU02 has an effective concentration of 0.1-10 μM and an IC50 of approximately 1μM. PU02 acts through a transmembrane site situated between two subunits. The Ser248, Leu288, Ile290, Thr294, and Gly306 residues are identified as important molecular determinants of PU02 activity. It is suggested that the naphthalene group of PU02 docks into the hydrophobic cavity formed by these molecular determinants. Specific mutations of Ser248, Thr294, and Gly306 convert PU02 into a complex modulator, promoting and inhibiting 5-HT-evoked signaling through these mutated sites at low and high concentrations, respectively. The PU02 binding site in the 5-HT3 receptor corresponds to allosteric sites in other anionic Cys-loop receptors. The dramatic changes in the functional properties of PU02 induced by subtle changes in its binding site exhibit that delicate structural can alternate between allosteric inhibition and potentiation of 5-HT and other Cys-loop receptors2.
