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Volume 4, Issue 2 American Journal of Ethnomedicine
ISSN 2348-9502
Natural Products Congress & World Pharma Congress 2017
October 16-18, 2017
3rd World Congress on
NATURAL PRODUCTS CHEMISTRY AND RESEARCH
&
12th WORLD PHARMA CONGRESS
October 16-18, 2017 Budapest, Hungary
Novel drug pharmacology for targeting dopamine signaling in the brain through ghrelin and
dopamine receptor heterodimers
Andras Kern
Scripps Research Institute Florida, USA
Amajor challenge in the field of G-Protein Coupled Receptor (GPCR) drug discovery in CNS is developing specific drugs without
side effects. Selection of a drug candidate is traditionally based on canonical signal transduction pathways after expression of
the individual GPCRs in heterologous cell lines. However, these assays do not predict the response of target cells in the native tissue;
therefore, the desired clinical outcome is often not met. For example, drugs designed for dopamine (DA) receptor subtypes act
on all neurons expressing this subtype, but selectivity requires knowledge of a specific target that discriminates between neuronal
subtypes. In neurons, the targeted GPCR is frequently not present in isolation, but with other GPCRs. Some GPCRs are capable of
forming heterodimers with a specific GPCR partner resulting in cell and tissue specific modification of canonical signal transduction.
To achieve more selectivity for regulating DA signaling, our research focused on regulating DA signaling by target neurons that
express dopamine receptor (D1R or D2R) and ghrelin receptor (GHSR1a) heterodimers. We exploit the novel concept that in GPCR
heterodimers a neutral antagonist of one protomer can modify the function of the partner protomer by an allosteric mechanism. We
detected that D2R:GHSR1a and D1R:GHSR1a heterodimers exist in neurons of native brain tissue resulting in allosteric modification
of DA signaling. Our results show that dopamine receptor heterodimers in hypothalamus can regulate food intake in animals through
D2R:GHSR1a. We found that in hippocampus D1R:GHSR1a heterodimers regulate DA-dependent memory performance. We show
DA signaling through these heterodimers is modulated by a GHSR1a antagonist. Hence, treatment with a GHSR1a antagonist
provides a selective way of blocking or enhancing DA signaling in neurons expressing the heterodimers without affecting signaling in
neurons expressing D1R or D2R alone. These results show potential opportunities for developing more selective therapeutic agents
for treating psychiatric disorders involving abnormal DA signaling.
Biography
Andras Kern completed his PhD in Genetics at Eotvos Lorand University, Hungary. He is currently working as Staff Scientist and studying the ghrelin receptor
signaling in neuronal tissue at Scripps Research Institute (TSRI).
Andras Kern, American Journal of Ethnomedicine, 4:2
DOI: 10.21767/2348-9502-C1-002