Document Type

Article

Original Publication Date

2017

Journal/Book/Conference Title

JOURNAL OF NEUROCHEMISTRY

Volume

141

Issue

4

First Page

577

Last Page

591

DOI of Original Publication

10.1111/jnc.14021

Comments

Originally published at http://doi.org/10.1111/jnc.14021

Date of Submission

June 2017

Abstract

The excitability of the central nervous system depends largely on the surface density of neurotransmitter receptors. The endocannabinoid receptor 1 (CB1R) and the metabotropic glutamate receptor mGlu(8)R are expressed pre-synaptically where they reduce glutamate release into the synaptic cleft. Recently, the CB1R interacting protein cannabinoid receptor interacting protein 1a (CRIP1a) was identified and characterized to regulate CB1R 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, CB1R and mGlu(8a)R. Five amino acids within the CB1R C-terminus were required and sufficient to reduce constitutive CB1R endocytosis by about 72% in the presence of CRIP1a. Interestingly, a similar sequence is present in mGlu(8a)R and consistently, endocytosis of mGlu(8a)R depended on CRIP1a, as well. Docking analysis and molecular dynamics simulations identified a conserved serine in CB1R (S468) and mGlu(8a)R (S894) that forms a hydrogen bond with the peptide backbone of CRIP1a at position R82. In contrast to mGlu(8a)R, the closely related mGlu(8b)R splice-variant carries a lysine (K894) at this position, and indeed, mGlu(8b)R endocytosis was not affected by CRIP1a. Chimeric constructs between CB1R, mGlu(8a)R, and mGlu(8b)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, CB1R and mGlu(8a)R.

Rights

© 2017 International Society for Neurochemistry, J. Neurochem.

Is Part Of

VCU Biochemistry and Molecular Biology Publications

Mascia_et_al-2017-Journal_of_Neurochemistry.sup-1.pdf (292 kB)
CRIP1a inhibits endocytosis of G-protein coupled receptors activated by endocannabinoids and glutamate by a common molecular mechanism

Share

COinS