RESUMEN
Many diseases of the nervous system are accompanied by alterations in synaptic functions. Synaptic plasticity mediated by the endogenous cannabinoid system involves the activation of the cannabinoid receptor 1 (CB1R). The principles of CB1R signaling must be understood in detail for its therapeutic exploration. We detected the Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1) as a novel CB1R partner. SGIP1 is functionally linked to clathrin-mediated endocytosis and its overexpression in animals leads to an energy regulation imbalance resulting in obesity. We report that SGIP1 prevents the endocytosis of activated CB1R and that it alters signaling via the CB1R in a biased manner. CB1R mediated G-protein activation is selectively influenced by SGIP1, ß-arrestin associated signaling is changed profoundly, most likely as a consequence of the prevention of the receptor's internalization elicited by SGIP1.
Asunto(s)
Proteínas Portadoras/metabolismo , Endocitosis/fisiología , Receptor Cannabinoide CB1/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Encéfalo/metabolismo , Proteínas Portadoras/genética , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Endocitosis/efectos de los fármacos , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Neuronas/metabolismo , Ratas Wistar , Saccharomyces cerevisiae , Transfección , Técnicas del Sistema de Dos Híbridos , Arrestina beta 2/metabolismoRESUMEN
The assembly of two covalently linked monomers into dimeric complexes is a prerequisite for metabotropic glutamate receptor 1 (mGluR1) function. The former concept of a strictly homodimeric subunit contribution in metabotropic glutamate receptor complexes has recently been brought into question. Alternative splicing of the GRM1 gene results in expression of variants that vary within their intracellular C-termini. Here we bring evidence that the short mGluR1b variant is found preferentially in a complex with the long mGluR1a variant in the rodent brain. The mGluR1a and mGluR1b variants distribution overlaps in Purkinje cells and the two variants colocalize in their spines. However mGluR1a and mGluR1b show distinct sub-cellular localization when expressed alone in neurons. We discovered that trafficking of mGluR1b to distal dendrites is reliant on its association with mGluR1a and that the long C-terminus of mGluR1a within the mGluR1a/b dimer is necessary for trafficking of the complex.
