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A Scaffold for the D1 Dopamine Receptor

An important issue in understanding cell regulation is how the more than 600 G protein-coupled receptors found in mammalian genomes are organized in cells to generate specific responses to extracellular signals. One mechanism for this organization is via association with scaffolding proteins that can direct the receptors' interactions with other proteins, their signaling properties, and their intracellular trafficking. One of these scaffolding proteins is PSD-95. Located in the postsynaptic densities of central synapses, PSD-95 regulates N-methyl-D-aspartate receptor internalization, synaptic transmission, and plasticity and plays essential roles in learning.

D1 co-localizes with PSD-95.

In this Paper of the Week, Jingping Zhang and colleagues show that PSD-95 interacts with the D1 dopamine receptor to regulate its trafficking and function. Interestingly, this interaction is mediated by the carboxyl-terminal tail of D1 and the N terminus of PSD-95, a region of PSD-95 that has only recently been recognized as a participant in protein-protein interaction. Co-expression of PSD-95 with D1 inhibited D1-mediated cAMP accumulation by reducing D1 expression at the cell surface. In addition, genetically engineered mice lacking PSD-95 showed a heightened behavioral response to either a D1 agonist or the psychostimulant amphetamine. These studies characterize a potential site for coordinating glutamatergic and dopaminergic signaling and are likely to have a consequence for mechanisms involved in substance dependence and abuse.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 15778-15789

Ubiquitin and the Immune Response

Deubiquitinating enzymes (DUB) form a family of cysteine proteases that digest ubiquitin chains and reverse the process of protein ubiquitination. Despite the identification of a large number of DUBs, their physiological functions remain poorly defined.

CYLD-deficient mice develop lymphoid organ abnormalities.

In this Paper of the Week, Wei Jin and colleagues provide new and important information on the DUB enzyme CYLD and its role in NF-B regulation and maintenance of the B cell phenotype. They found that CYLD-deficient B cells are hyperproliferative when stimulated in vitro and display elevated levels of antigen responses in vivo. The cells also exhibit constitutive activation of the transcription factor NF-B. In addition, CYLD^-/^- mice develop B cell hyperplasia and lymphoid organ abnormalities. These findings establish CYLD as a key regulator of B cell activation and development and reveal a physiological function for CYLD in NF-B regulation.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 15884-15893

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