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Dopamine receptor D3 affects the expression of Period1 in mouse cells via DRD3-ERK-CREB signaling
Masaki Matsuda1, Takumi Nishi2, Yuya Yoshida2
1Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Abstract:
Circadian rhythm alterations are related to the onset and severity of various diseases. The expression of the dopamine receptor D3 (DRD3) is regulated by clock genes, and DRD3 functional abnormalities are linked to various neurological diseases. However, the relationship between DRD3 function and circadian machinery is unclear. Here, we demonstrate the influence of DRD3 on the circadian machinery. Although the expression of DRD3 in mouse suprachiasmatic nucleus (SCN) did not show a circadian rhythm, the expression of Per1 mRNA was altered in the SCN of Drd3 knockout (Drd3-/-) mice compared to that in wild-type (WT) mice. These differences were caused by the upregulation of the DRD3-extracellular signal-regulated kinase-cAMP response element binding protein (DRD3-ERK-CREB) signaling pathway in cultured cells and SCN. In addition, Drd3-/- mice demonstrated increased period length of locomotor activity than WT mice only under constant dark conditions. Expression of clock genes in the liver, which does not express DRD3, was affected by the loss of DRD3 only under constant dark conditions, similar to that in the SCN. These results suggest that DRD3 expressed in the SCN regulates the central clock via endogenous ligands and affects peripheral organs. This may provide new evidence to unravel the relationship between dopamine neurotransmission and the circadian clock, which has not yet been fully elucidated.
Insights
Dopamine receptor D3 (DRD3) influences the body's internal clock. Loss of DRD3 alters clock gene expression and activity rhythms, impacting neurological health and circadian regulation.
Area of Science:
- Neuroscience
- Chronobiology
- Molecular Biology
Background:
- Circadian rhythm disruptions are linked to various diseases.
- Dopamine receptor D3 (DRD3) abnormalities are associated with neurological disorders.
- The interplay between DRD3 function and the circadian clock remains largely unknown.
Purpose of the Study:
- To investigate the influence of Dopamine receptor D3 (DRD3) on the circadian machinery.
- To elucidate the molecular mechanisms underlying DRD3's effect on circadian rhythms.
- To explore the role of DRD3 in regulating central and peripheral clocks.
Main Methods:
- Utilized Drd3 knockout (Drd3-/-) and wild-type (WT) mice.
- Analyzed Per1 mRNA expression in the suprachiasmatic nucleus (SCN).
- Investigated the DRD3-ERK-CREB signaling pathway in cultured cells and SCN.
- Measured locomotor activity rhythms under constant dark conditions.
- Examined clock gene expression in the liver.
Main Results:
- Per1 mRNA expression was altered in the SCN of Drd3-/- mice compared to WT mice.
- The DRD3-ERK-CREB signaling pathway was upregulated in cultured cells and SCN of Drd3-/- mice.
- Drd3-/- mice exhibited a longer period of locomotor activity under constant dark conditions.
- Loss of DRD3 affected clock gene expression in the liver, particularly under constant dark conditions.
Conclusions:
- DRD3 in the SCN regulates the central circadian clock, potentially via endogenous ligands.
- DRD3 signaling impacts peripheral clock gene expression in organs like the liver.
- These findings offer new insights into the relationship between dopamine neurotransmission and circadian clock regulation.
