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Zsolt LENKEI"Activation-dependent plasticity of polarized GPCR distribution in neurons"

Abstract :

Targeting mechanisms to the somatodendritic and axonal plasma membrane remain unknown for the
majority of neuronal G-protein coupled receptors (GPCRs). In order to precisely evaluate the role of
GPCR conformation in the regulation of sub-neuronal distribution, we have measured in axons and dendrites of cultured hippocampal neurons the steady-state distribution and the endocytosis rate of a
GPCR displaying a wide range of conformational states, obtained by mutational or pharmacological
manipulation of the type-1 cannabinoid receptor (CB1R). We show that a non-linear relationship between GPCR activation and sub-domain specific endocytosis rates leads to surprisingly high activation-
dependent plasticity in surface distribution phenotypes. Mathematical modeling shows that modulation of the steady-state rate of somatodendritic endocytosis is sufficient to reproduce experimental phenotypes.

In consequence, for GPCRs lacking dominant targeting or anchoring motifs, pharmacological activation state is likely an important determinant of polarized sub-neuronal distribution. Indeed, moderate level of chronic pharmacological activation of somatodendritic somatostatin SST2A receptors leads to the emergence of a previously unexpected axonally polarized phenotype.

Selected publications

Time-gated total internal reflection fluorescence microscopy with a supercontinuum excitation source.Blandin P, Lévêque-Fort S, Lécart S, Cossec JC, Potier MC, Lenkei Z, Druon F, Georges P.Appl Opt. 2009 Jan 20;48(3):553-9.    

The type 1 cannabinoid receptor is highly expressed in embryonic cortical projection neurons and negatively regulates neurite growth in vitro.Vitalis T, Lainé J, Simon A, Roland A, Leterrier C, Lenkei Z.Eur J Neurosci. 2008 Nov;28(9):1705-18.
Targeting of the 5-HT1A serotonin receptor to neuronal dendrites is mediated by Yif1B.Carrel D, Masson J, Al Awabdh S, Capra CB, Lenkei Z, Hamon M, Emerit MB, Darmon M.J Neurosci. 2008 Aug 6;28(32):8063-73.