期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 49, 页码 38659-38666出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M005938200
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资金
- NHLBI NIH HHS [HL16037] Funding Source: Medline
- NIGMS NIH HHS [GM60982] Funding Source: Medline
The beta (1)-adrenergic receptor (beta (1)AR) is the most abundant subtype of beta -adrenergic receptor in the mammalian brain and is known to potently regulate synaptic plasticity. To search for potential neuronal beta (1)AR-interacting proteins, we screened a rat brain cDNA library using the beta (1)AR carboxyl terminus (beta (1)AR-CT) as bait in the yeast two-hybrid system. These screens identified PSD-95, a multiple PDZ domain-containing scaffolding protein, as a specific binding partner of the beta (1)AR-CT. This interaction was confirmed by in vitro fusion protein pull-down and blot overlay experiments, which demonstrated that the beta (1)ARCT binds specifically to the third PDZ domain of PSD-95, Furthermore, the full-length beta (1)AR associates with PSD-95 in cells, as determined by co-immunoprecipitation experiments and immunofluorescence co-localization studies. The interaction between beta (1)AR and PSD-95 is mediated by the last few amino acids of the beta (1)AR, and mutation of the beta (1)AR carboxyl terminus eliminated the binding and disrupted the co-localization of the beta (1)AR and PSD-95 in cells. Agonist-induced internalization of the beta (1)AR in HEK-293 cells was markedly attenuated by PSD-95 co-expression, whereas co-expression of PSD-95 has no significant effect on either desensitization of the beta (1)AR or beta (1)AR-induced cAMP accumulation. Furthermore, PSD-95 facilitated the formation of a complex between the beta (1)AR and N-methyl-D-aspartate receptors, as assessed by co-immunoprecipitation. These data reveal that PSD-95 is a specific beta (1)AR binding partner that modulates beta (1)AR function and facilitates physical association of the beta (1)AR with synaptic proteins, such as the N-methyl-D-aspartate receptors, which are known to be regulated by beta (1)AR stimulation.
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