From GPCR to RTK to NMDAR

Abstract

In the hippocampus, dopamine signaling can inhibit or stimulate excitatory synaptic transmission, affecting the formation of long-term potentiation (LTP), a possible mechanism underlying learning and memory. Dopamine receptors are also important for their role in mental disorders and are the target of many antipsychotic agents. Kotecha et al. provide evidence that dopamine signaling through the D4 receptor, a G protein-coupled receptor, may activate the receptor tyrosine kinase (RTK) platelet-derived growth factor receptor β (PDGFRβ) to mediate inhibition of N -methyl-D-aspartate receptor (NMDAR) activity. D4 receptors belong to the larger D2 family of dopamine receptors, and application of the D2 selective agonist quinpirole to cultured hippocampal neurons depressed NMDAR current with delayed kinetics, suggesting mediation through a multistep signaling pathway, not direct inhibition of the NMDA channel. This inhibition required G protein signaling and was blocked by agents that prevented activation of the PDGFRβ, suggesting that the dopamine receptor was transactivating the RTK to cause NMDAR current suppression. Further pharmacological dissection of the pathway suggested that the activation of phospholipase C and the subsequent increase in intracellular calcium concentration [through activation of inositol trisphosphate receptors (IP3Rs)] by PDGFRβ was required for NMDAR inhibition mediated by stimulation of the dopamine receptors. Confirmation of this pathway was obtained by analysis of quinpirole inhibition of NMDAR currents in hippocampal slice preparations, which also required the activation of PDGFRβ, PLC, and IP3R. Activated (phosphorylated) PDGFRβ was also detected in slices after quinpirole application and downstream signaling proteins of the PDGFRβ cascade were also activated. Thus, dopamine acting through D2 receptors may be able to depress excitatory synaptic transmission in the hippocampus by inhibiting NMDAR activity through transactivation of PDGFRβ. This is in contrast to the effect of dopamine acting through D1 receptors, which stimulates a protein kinase A pathway that potentiates excitatory synaptic transmission in the hippocampus. S. A .Kotecha, J. N. Oak, M. F. Jackson, Y. Perez, B. A. Orser, H. H. M. Van Tol, J. F. McDonald, A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron 35 , 1111-1122 (2002). [Online Journal]