parkinson-2017-posters-accepted-abstracts

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September 25-26, 2017 Chicago, USA

International Conference on

Parkinson’s disease and Movement Disorders

Volume 7, Issue 5 (Suppl)

J Alzheimers Dis Parkinsonism, an open access journal

ISSN: 2161-0460

Parkinson 2017

September 25-26, 2017

J Alzheimers Dis Parkinsonism 2017, 7:5 (Suppl)

DOI: 10.4172/2161-0460-C1-031

Multiple GPCR heteroreceptor complexes: New targets for treatment of Parkinson´s diseases

Dasiel O Borroto-Escuela

and

Kjell Fuxe

Karolinska Institutet, Sweden

he introduction of allosteric receptor–receptor interactions in GPCR heteroreceptor complexes of the CNS gave a new

dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed

to be based on the reorganization of the homo- and heteroreceptor complexes in the post junctional membrane of synapses.

Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription

factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network

(GPCR-HetNet) indicated that the allosteric receptor-receptor interactions dramatically increase GPCR diversity and biased

recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can

lead to brain disease. The findings of dopamine (D2R) and adenosine (A2AR) hetero and isoreceptor complexes in the brain

over the last decade gave new targets for drug development in Parkinson´s diseases. We studied the possible reorganization of

the A2A-A2A homoreceptor complex and the A2AR-D2R, A2AR-mGluR5 heteroreceptor complexes in the dorsal and ventral

striatum in the hemiparkinson rat using the proximity ligation assay. The results were obtained in the dorsolateral striatum

comparing the 6-OHDA lesioned side with the unlesioned side, 4 weeks after the lesion (6-OHDA microinjections into the

medial forebrain bundle). The A2AR-D2R heteroreceptor complex was found to be significantly increased on the lesioned side

( p< 0.05, Student’s paired t-test , N= 4 rats), which was true also for the A2AR-mGluR5 heteroreceptor complex (p< 0.05,

Student’s paired t-test , N= 4 rats) . The A2AR-A2AR homoreceptor complex was not significantly altered on the lesioned side

vs the unlesioned side. Thus, the loss of DA terminals and DA transmission in the dorsal striatum on the lesioned side leads to

an altered balance of the hetero and homoreceptor complexes with significant increases of the A2AR-D2R and A2AR-mGluR5

heteroreceptor complexes on the lesioned side. In contrast, the A2AR-A2AR homoreceptor complexes were not altered on

the lesiond side vs the unlesioned side. These results may be interpreted as indicating that in the untreated hemiparkinsonian

rat the A2AR-D2R and A2AR-mGluR5 heteroreceptor complexes become more dominant favoring excitation of the dorsal

striato-pallidal GABA neurons mediating motor inhibition. Hypokinesia becomes increased. The hypothesis is given that

changes in the function of the dopamine and adenosine heteroreceptor complexes may especially help us understand the

molecular mechanisms underlying the motor complications of long-term therapy in Parkinson’s disease (PD) with levodopa

and DA receptor agonists. In the indirect pathway the potential role of the A2AR-D2R, A2AR-D2R-mGluR5 and D2R-NMDAR

heteroreceptor complexes in PD are covered.