CRIP1a inhibits endocytosis of G-protein coupled receptors activated by endocannabinoids and glutamate by a common molecular mechanism
Mascia F, Klotz L, Lerch J, Ahmed MH, Zhang Y, Enz R (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 141
Pages Range: 577-591
Journal Issue: 4
DOI: 10.1111/jnc.14021
Abstract
The excitability of the central nervous system depends largely on the surface density of neurotransmitter receptors. The endocannabinoid receptor 1 (CB1 R) and the metabotropic glutamate receptor mGlu8 R are expressed pre-synaptically where they reduce glutamate release into the synaptic cleft. Recently, the CB1 R interacting protein cannabinoid receptor interacting protein 1a (CRIP1a) was identified and characterized to regulate CB1 R activity in neurons. However, underlying molecular mechanisms are largely unknown. Here, we identified a common mechanism used by CRIP1a to regulate the cell surface density of two different types of G-protein coupled receptors, CB1 R and mGlu8a R. Five amino acids within the CB1 R C-terminus were required and sufficient to reduce constitutive CB1 R endocytosis by about 72% in the presence of CRIP1a. Interestingly, a similar sequence is present in mGlu8a R and consistently, endocytosis of mGlu8a R depended on CRIP1a, as well. Docking analysis and molecular dynamics simulations identified a conserved serine in CB1 R (S468) and mGlu8a R (S894) that forms a hydrogen bond with the peptide backbone of CRIP1a at position R82. In contrast to mGlu8a R, the closely related mGlu8b R splice-variant carries a lysine (K894) at this position, and indeed, mGlu8b R endocytosis was not affected by CRIP1a. Chimeric constructs between CB1 R, mGlu8a R, and mGlu8b R underline the role of the identified five CRIP1a sensitive amino acids. In summary, we suggest that CRIP1a negatively regulates endocytosis of two different G-protein coupled receptor types, CB1 R and mGlu8a R.
Authors with CRIS profile
Fabrizio Mascia
Lehrstuhl für Biochemie und Molekulare Medizin
Lisa Klotz-Weigand
Lehrstuhl für Biochemie und Molekulare Medizin
Ralf Enz
Professur für Biochemie und Medizinische Molekularbiologie
Involved external institutions
United States (USA) (US)How to cite
APA:
Mascia, F., Klotz, L., Lerch, J., Ahmed, M.H., Zhang, Y., & Enz, R. (2017). CRIP1a inhibits endocytosis of G-protein coupled receptors activated by endocannabinoids and glutamate by a common molecular mechanism. Journal of Neurochemistry, 141(4), 577-591. https://doi.org/10.1111/jnc.14021
MLA:
Mascia, Fabrizio, et al. "CRIP1a inhibits endocytosis of G-protein coupled receptors activated by endocannabinoids and glutamate by a common molecular mechanism." Journal of Neurochemistry 141.4 (2017): 577-591.
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