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Anita Aperia"Tracking G-protein coupled receptors in dendrites"

Abstract :


The trafficking of receptors in and out of synapses may be a means to regulate receptor function and plasticity. We are interested in how G-protein coupled receptors (GPCR), that may be potential targets for drugs in neuropsychiatric diseases, reach their functional sites.
Most of the studies I will be discussing have been performed on cultured slices from striatum or hippocampus, transfected with GPCRs fused to fluorescent proteins.

The dopaminergic and glutamatergic systems interact to initiate and organize normal behavior, a communication that may be perturbed in many neuropsychiatric diseases, including schizophrenia. We have shown that NMDA, by allosterically modifying NMDA receptors, can act as a scaffold to recruit laterally diffusing dopamine D1 receptors (D1R) to neuronal spines (Proc Natl Acad Sci U S A. 2006 103:762). Such a diffusion trap system represents a molecular mechanism for brain plasticity and offers a promising target for development of antipsychotic therapy. Interestingly the effect is specific for the D1 receptor, which belongs the class of D1 like receptors, and is not observed with the D5 receptor, which also belongs to the class of D1 like receptors. 
Lateral diffusion in the plasma membrane appears to be the main transport pathway in dendrites for most of the GPCRs that we have studied. This applies for the D1, D2 and D5 receptors, the metabotropic glutamate receptor5, which has also been implicated in the pathogenesis of schizophrenia, and the 5-HT 1A receptor, implicated in the pathogenesis of depression. In contrast, the 5-HT1B receptor was found to be mainly transported in dendrites via vesicles. Interestingly, both mGluR5 and 5-HTiB are dependent on the interaction with a non-receptor protein for their proper insertion in the membrane. The question to which extent brain plasticity will be dependent on the mode of transport of GPCRs and the kind of proteins that they will physically interact with will be discussed.

Selected publications

Developmental changes in frequency of the ciliary somatostatin receptor 3 protein. Stanić D, Malmgren H, He H, Scott L, Aperia A, Hökfelt T. Brain Res. 2009 Jan 16;1249:101-12. Epub 2008 Nov 1.
    
Interaction between N-methyl-d-aspartic acid receptors and D1 dopamine receptors: An important mechanism for brain plasticity.Scott L, Aperia A.Neuroscience. 2008 Oct 18. [Epub ahead of print]
   
Negative reciprocity between angiotensin II type 1 and dopamine D1 receptors in rat renal proximal tubule cells.Khan F, Spicarová Z, Zelenin S, Holtbäck U, Scott L, Aperia A.Am J Physiol Renal Physiol. 2008 Oct;295(4):F1110-6. Epub 2008 Aug 13.