Robust GRK2/3/6-dependent desensitization of oxytocin receptor in neurons

Jun 17, 2024iScience

Strong reduction of oxytocin receptor response in neurons depending on GRK2, GRK3, and GRK6 proteins

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Abstract

Robust and rapid-onset desensitization of oxytocin receptors was identified in multiple regions of the mouse brain.

Oxytocin receptors (OXTR) show desensitization in response to agonists in neurons.
Both individual neuron activity and presynaptic signaling are affected by this desensitization.
G-protein-coupled receptor kinases (GRK2, GRK3, GRK6) are recruited to activated OXTR in neurons.
Inhibition of GRK2/3/6 kinase activity disrupts the desensitization process of OXTR.
Agonist-induced internalization of OXTR occurs via recruitment to early endosomes, which is also affected by GRK inhibition.

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Oxytocin plays critical roles in the brain as a neuromodulator, regulating social and other affective behavior. However, the regulatory mechanisms controlling oxytocin receptor (OXTR) signaling in neurons remain unexplored. In this study, we have identified robust and rapid-onset desensitization of OXTR response in multiple regions of the mouse brain. Both cell autonomous spiking response and presynaptic activation undergo similar agonist-induced desensitization. G-protein-coupled receptor kinases (GRK) GRK2, GRK3, and GRK6 are recruited to the activated OXTR in neurons, followed by recruitment of β-arrestin-1 and -2. Neuronal OXTR desensitization was impaired by suppression of GRK2/3/6 kinase activity but remained unaltered with double knockout of β-arrestin-1 and -2. Additionally, we observed robust agonist-induced internalization of neuronal OXTR and its Rab5-dependent recruitment to early endosomes, which was impaired by GRK2/3/6 inhibition. This work defines distinctive aspects of the mechanisms governing OXTR desensitization and internalization in neurons compared to prior studies in heterologous cells.

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Robust GRK2/3/6-dependent desensitization of oxytocin receptor in neurons

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