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Molecular mechanisms regulating the development of physiological and behavioral tolerance to cannabinoids are not well understood. Two cellular correlates implicated in the development and maintenance of tolerance are CB(1) cannabinoid receptor internalization and uncoupling of receptor signal transduction. Both processes have been proposed as mediators of tolerance because of observations that chronic Delta(9)-tetrahydrocannabinol (THC) treatment causes both region-specific decreases in CB(1) receptors and G-protein coupling in the brain. To determine the balance of these two processes in regulating CB(1) receptor signaling during sustained receptor stimulation, we evaluated the parameters affecting ERK1/2 MAP kinase activity in HEK293 cells stably expressing CB(1) receptors. CB(1) receptor stimulation by the potent CB(1) receptor agonist, CP 55,940 transiently activated ERK1/2. To determine if CB(1) receptor desensitization or internalization was responsible for the transient nature of ERK1/2 activation, we evaluated ERK1/2 phosphorylation in HEK293 cells expressing a desensitization-deficient CB(1) receptor (S426A/S430A CB(1)). Here, the duration of S426A/S430A CB(1) receptor-mediated activation of ERK1/2 was markedly prolonged relative to wild-type receptors, and was dynamically reversed by SR141716A. Interestingly, the S426A/S430A CB(1) receptor was still able to recruit betaarrestin-2, a key mediator of receptor desensitization, to the cell surface following agonist activation. In contrast to a central role for desensitization, pharmacological and genetic approaches suggested CB(1) receptor internalization is dispensable in the transient activation of ERK1/2. This study indicates that the duration of ERK1/2 activation by CB(1) receptors is regulated by receptor desensitization and underscores the importance of G-protein uncoupling in the regulation of CB(1) receptor signaling.
Pubmed ID: 17681354 RIS Download
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Software tool for automated microscope acquisition, device control, and image analysis. Used for integrating dissimilar fluorescent microscope hardware and peripherals into a single custom workstation, while providing all the tools needed to perform analysis of acquired images. Offers user friendly application modules for analysis such as cell signaling, cell counting, and protein expression.
View all literature mentionsOrganization which manufactures bacteria for research and clinical investigations. List Biological Laboratories cultivates native and recombinant microorganisms and purifies, formulates, and lyopholizes enzyme products, virulence factors, and microbial cell wall components. Products include antibodies, microbial toxins, peptides, and virulence factors. Services include live biotherapeutics for clinical trials, contracting research capabilities, GMP regulatory support, lyopholization services and support, and toxin compliance.
View all literature mentionsOrganization which manufactures bacteria for research and clinical investigations. List Biological Laboratories cultivates native and recombinant microorganisms and purifies, formulates, and lyopholizes enzyme products, virulence factors, and microbial cell wall components. Products include antibodies, microbial toxins, peptides, and virulence factors. Services include live biotherapeutics for clinical trials, contracting research capabilities, GMP regulatory support, lyopholization services and support, and toxin compliance.
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