Axonal Targeting of the 5-HT1B Serotonin Receptor Relies on Structure-Specific Constitutive Activation

authors

• Carrel Damien
• Simon Anne
• Emerit Michel
• Rivals Isabelle
• Leterrier Christophe
• Biard Marc
• Hamon Michel
• Darmon Michèle
• Lenkei Zsolt

keywords

• Axon
• Constitutive activity
• Polarized distribu
• Tion
• Targeting
• Third intracellular loop
• 7-transmembrane receptor
• P11

abstract

. By analogy to other axonal proteins, transcytotic delivery following spontaneous endocytosis from the somatoden-dritic membrane is expected to be essential for polarized distribution of axonal G-protein coupled receptors (GPCRs). However, possible contribution from constitu-tive activation, which may also result in constitutive GPCR endocytosis, is poorly known. Using two closely related but differentially distributed serotonin receptors, here we demonstrate higher constitutive activation and spontaneous endocytosis for the axonal 5-HT 1B R, as compared to the somatodendritic 5-HT 1A R, both in non-neuronal cells and neurons. Activation-dependent consti-tutive endocytosis is crucial for axonal targeting, because inverse-agonist treatment, which prevents constitutive activation, leads to atypical accumulation of newly synthesized 5-HT 1B Rs on the somatodendritic plasma membrane. Using receptor chimeras composed of different domains from 5-HT 1A R and 5-HT 1B R, we show that the complete third intracellular loop of 5-HT 1B R is necessary and sufficient for constitutive activation and efficient axonal targeting, both sensitive to inverse-agonist treatment. These results suggest that activation and targeting of 5-HT 1B Rs are intimately interconnected in neurons.

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