Neuropharmacology

Biography

Biography: David K Grandy

Abstract

Originally known only to late 19th century chemists and students of fermentation and putrefaction, the noncatecholic biogenic amines (NBAs) entered the scientific main stream in the first decade of the 20th century with Barger and Dale’s groundbreaking studies demonstrating the profound pressor properties of -phenylethylamine and p-tyramine. However, unlike their close relatives the catecholamines, NBAs came to be regarded as ‘false transmitters’ and it would be nearly a century before these so-called ‘trace amines’ had a receptor of their own. Reported independently in 2001 by two groups the G protein-coupled receptor, now referred to as trace amine-associated receptor 1 (TAAR1), is the best-characterized member of a human gene family consisting of 9 members. Depending on the cellular environment heterologously expressed TAAR1 couples to cAMP production, mobilization of intracellular calcium, and chloride conductance. Unexpectedly, TAAR1-mediated signaling is constitutive exerting an inhibitory tone on mouse midbrain dopamine neurons. The capacity to express TAAR1 in vitro and the ability to assay its activation in multiple ways resulted in the compilation of a comprehensive pharmacological profile that challenges current concepts regarding the mechanism of action of several medically important drugs including amphetamine, methamphetamine, Ecstasy, apomorphine, and dopamine and its supposed inactive metabolite, 3-methoxytyramine. Given its pharmacological profile and anatomic distribution commercial high throughput screening efforts were initiated and several TAAR1-selective compounds were identified. With these new tools the receptor’s basic biology can now be explored in intact animals and the clinical value of pharmacologically manipulating its signaling in the context of mental health, evaluated.