Title:Tartaric Acid Enhances Adrenergic Receptor Activity: Test of a General Theory of Extracellular Aminergic GPCR Enhancer Discovery
VOLUME: 11 ISSUE: 4
Author(s):Robert Root-Bernstein, Jenna Fewins and Patrick F. Dillon
Affiliation:Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Keywords:Ascorbate, enhancers, epinephrine, fade, norepinephrine, tachyphylaxis, tartrate.
Abstract:Several different classes of compounds enhance the potency of aminergic receptor ligands
three-fold or more and increase their duration of activity up to ten-fold. These enhancers include the
vitamins ascorbic acid and folic acid, chelators such as ethylenediaminetetraacetic acid,
corticosteroids, and opioids, opiates and opiate antagonists. We have previously demonstrated that all
of these classes of enhancers share a common molecular motif consisting of a linear array of two
hydroxyls and a carbonyl. We demonstrate here that because of this common molecular motif, all
compounds known to enhance aminergic receptor ligands bind to highly conserved regions of the first
or second extracellular loops of aminergic receptors at physiologically or pharmacologically relevant
concentrations. These compounds also bind directly to aminergic ligands with significant specificity
and affinity. These results suggest three very simple, complementary methods for screening for novel
extracellular aminergic receptor enhancers: 1) in silico screening for the presence of the common
aminergic receptor enhancer motif; 2) screening for binding to the aminergic ligand of choice; and 3)
screening for binding to receptor peptides representing the enhancer binding site on the receptor.
Using these three complementary methods, we predict a new class of enhancers (tartaric acids) and
demonstrate the predicted enhancement in an in vitro smooth muscle assay.
