Molecular and cellular events of dopamine D1 receptor‐mediated tau phosphorylation in SK‐N‐MC cells

Abstract

Microtubules are involved in the formation of axons and dendrites, maintenance of neuronal morphology, and cellular trafficking. Recent studies suggest that drugs affecting dopamine activity in the brain can induce cytoskeletal modifications. For instance, we have demonstrated in acute rat brain slices a molecular chain of events connecting dopamine D1 receptor to aberrant phosphorylation of the microtubule-associated protein tau. However, the molecular and cellular effects of tau phosphorylated by means of the activation of dopamine receptors were unexplored. Here we used SK-N-MC cells, which express endogenously functional D1 receptors, to demonstrate that levels of phosphorylated tau at serines 199-202 or 214 are increased by a calcium-dependent pathway subsequent to D1 receptor stimulation. Using selective pharmacological tools, we showed that enhanced intracellular calcium lead to cyclin-dependent kinase 5 (cdk5) activation, by calpain proteolysis of p35 to p25, as well as glycogen synthase kinase 3β (GSK3β) activation, by its phosphorylation at tyrosine 216. Interestingly, while the activation of protein kinase A (PKA) led directly to the phosphorylation of tau at serine 214, tau phosphorylation at serines 199-202 was independent of PKA. In addition, inhibition of cdk5 or GSK3β prevented the decrease in cell viability induced by D1 receptor stimulation whereas PKA inhibition had no influence. Our data demonstrate that activation of cdk5 and GSK3β following D1 receptor stimulation could have profound influence on both the neuronal cytoskeletal constituent tau and cell survival in SK-N-MC cells.

γ-Aminobutyric Acid Type A (GABAA) Receptor Activation Modulates Tau Phosphorylation

“…Other neurotransmitter receptor systems have so far not been implicated in the regulation of Tau phosphorylation with the exception of dopamine. In SK-N-MC cells and striatal neurons, Tau was phosphorylated at Ser-199/Ser-202 in response to dopamine D1 receptor activation in a Ca 2ϩ -and PKA-dependent manner (41,42). Interestingly, we found that GABA A receptor activators, as well as a dopamine D1/D2 receptor antagonist, increased Pin1-Tau interaction and Tau phosphorylation at Ser-199/Ser-202/Thr-205 (in case of GABA A activation; the dopamine D1/D2 antagonist was not analyzed further in this study).…”

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

“…In addition, the variants in the gene encoding CK1 that phosphorylate DARPP-32 are associated with the subjective response to amphetamine in normal volunteers (Veenstra-VanderWeele et al, 2006). The other kinases that are related to the DARPP-32 signaling network, CDK5 and ERK, have been shown to contribute to the abnormal plasticity that leads to drug abuse and L-DOPA-induced dyskinesia (Aubert et al, 2005;Girault et al, 2007;Santini et al, 2007;Lebel and Cyr, 2011); however, further observations in clinical settings are necessary to support these hypotheses.…”

Amisulpride as a potential disease‐modifying drug in the treatment of tauopathies

“…In addition to its affinity for 5‐HT7R, amisulpride also targets dopaminergic receptors that, in turn, may influence tau aggregation 31–33 . To exclude the involvement of dopaminergic signaling, we analyzed the effects of dopamine D2/D3 antagonist tiapride.…”