Plasticity of the dopamine1 receptor and its signaling pathway

University dissertation from Stockholm : Karolinska Institutet, Department of Women's and Children's Health

Abstract: Dopamine 1 receptor (D1R) belongs to the G protein coupled receptor superfamily with seven transmembrane domains. Previous studies from our laboratory showed that D1R availability in the plasma membrane of renal epithelial cells is dynamically regulated by the dopaminergic tonus. Here, we 'examined the availability of D1R in the brain. In medium spiny neurons from striatum, acute activation of NMDA receptors sensitized D1R to the plasma membrane and spines. D1R was functionally active since dopamine-sensitive adenylyl cyclase activity was increased after NMDA treatment. In renal epithelial cells, D1R sensitization was dependent on an intact microtubule cytoskeleton. When microtubules, but not actin filaments, were disrupted D1R transport to the plasma membrane was impaired. D1R transport to the plasma membrane was necessary for D1R to link to PLC-PKC signaling pathway. In the brain, more specifically in striatum and in hippocampus, NMDA enhanced the coupling of D1R to Gq/11. Under these conditions, D1R activation triggered a calcium signal via activation of PLC and release of calcium from intracellular stores. In this thesis we show that the ability of D1R to link to different signaling pathways is a dynamic regulated process. We provide new information about the signaling pathways linked to D1R and the way that this interaction is modulated by the availability of D1R in the plasma membrane. All together, the findings presented herein help to explain the broad spectrum of physiological actions triggered by D1R and may provide a new framework to account for pathophysiological conditions where abnormalities in the dopaminergic system are involved.

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