Abstract
The G-protein coupled receptor 139 (GPR139) is expressed specifically in the brain in areas of relevance for motor control. GPR139 function and signal transduction pathways are elusive, and results in the literature are even contradictory. Here, we examined the potential neuroprotective effect of GPR139 agonism in primary culture models of dopaminergic (DA) neuronal degeneration. We find that in vitro GPR139 agonists protected primary mesencephalic DA neurons against 1-methyl-4-phenylpyridinium (MPP+)-mediated degeneration. Protection was concentration-dependent and could be blocked by a GPR139 antagonist. However, the protection of DA neurons was not found against rotenone or 6-hydroxydopamine (6-OHDA) mediated degeneration. Our results support differential mechanisms of toxicity for those substances commonly used in Parkinson’s disease (PD) models and potential for GPR139 agonists in neuroprotection.
Highlights
The G protein-coupled receptor (GPCR) superfamily is the largest group of cell surface receptors
C(t) values using two different primer pairs for Gpr139 were in the same range as the C(t) value for tyrosine hydroxylase, the gene characteristic for DA neurons (Figure 7A)
We found that three different agonists dose-dependently and substantially protect primary DA neurons against MPP+ toxicity: between 40.5% and 42.8% of the cells killed by 1 μM MPP+ were rescued by previous incubation with 1 μM of either compound (Figure 8)
Summary
The G protein-coupled receptor (GPCR) superfamily is the largest group of cell surface receptors. Many GPCRs have been cloned without knowledge of their function and ligands (Davenport et al, 2013) and are likely to cover a number of future drug targets. One of these is the G protein coupled-receptor 139 (GPR139). It was found to belong to the class A GPCRs and to be highly conserved through different species including human, mouse, rat, chicken, fugu and zebrafish (Gloriam et al, 2005)
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