Gyógyszerészet, farmakogenomika, gyógyszerkutatás és tervezés, gyógyszeres kezelés
The trace amine-associated receptor 1 (TAAR1) is a Gs protein-coupled, intracellularly
located metabotropic receptor. Trace and classic amines, amphetamines, act as agonists
on TAAR1; they activate downstream signal transduction influencing neurotransmitter
release via intracellular phosphorylation. Our aim was to check the effect of the
catecholaminergic activity enhancer compound ((−)BPAP, (R)-(−)-1-(benzofuran-2-yl)-2-propylaminopentane)
on neurotransmitter release via the TAAR1 signaling. Rat striatal slices were prepared
and the resting and electrical stimulation-evoked [3H]dopamine release was measured.
The releaser (±)methamphetamine evoked non-vesicular [3H]dopamine release in a TAAR1-dependent
manner, whereas (−)BPAP potentiated [3H]dopamine release with vesicular origin via
TAAR1 mediation. (−)BPAP did not induce non-vesicular [3H]dopamine release. N-Ethylmaleimide,
which inhibits SNARE core complex disassembly, potentiated the stimulatory effect
of (−)BPAP on vesicular [3H]dopamine release. Subsequent analyses indicated that the
dopamine-release stimulatory effect of (−)BPAP was due to an increase in PKC-mediated
phosphorylation. We have hypothesized that there are two binding sites present on
TAAR1, one for the releaser and one for the enhancer compounds, and they activate
different PKC-mediated phosphorylation leading to the evoking of non-vesicular and
vesicular dopamine release. (−)BPAP also increased VMAT2 operation enforcing vesicular
[3H]dopamine accumulation and release. Vesicular dopamine release promoted by TAAR1
evokes activation of D2 dopamine autoreceptor-mediated presynaptic feedback inhibition.
In conclusion, TAAR1 possesses a triggering role in both non-vesicular and vesicular
dopamine release, and the mechanism of action of (−)BPAP is linked to the activation
of TAAR1 and the signal transduction attached.
