CRHR-1 signalling inhibits AMPA-receptor internalisation

The neuropeptide corticotropin-releasing hormone (CRH) is a key regulator of the organism´s overall response to stress. Limbic CRHR–1-signalling mediates anxiety-like behaviour, modulates hippocampal dependent learning and enhances fear conditioning. Further, CRH/CRHR–1 or stress has a facilitating effect on hippocampal long-term potentiation (LTP). However, very little is known about the molecular mechanisms by which CRHR–1 influences neural transmission efficacy. Hence, asking for putative interaction partners, we performed a yeast–2-hybrid screen using the C-terminal intracellular domain of CRHR–1. We identified the membran-associated guanylate kinase (MAGUK) postsynaptic density –95 (PSD –95) and synapse associated protein (SAP) –97 as potential interaction partners. As the major MAGUK localised in the postsynaptic density (PSD) of glutamatergic synapses, PSD–95 contributes to the compartimentalisation of the postsynpatic signalling machinery. By means of its three PDZ-domains, PSD–95 interacts with various ionotropic receptors exhibiting a PDZ-binding motif. We demonstrate an interaction between CRHR–1 and the MAGUKs PSD–95 and SAP–97 in vitro. We characterise the CRHR–1 PDZ-binding domain as essential for the delivery of the receptor to postsynaptic sites in primary hippocampal cultures. Further, testing the hypothesis whether CRHR–1-signalling has an impact on AMPAR-trafficking, we find that CRH-mediated activation of CRHR–1 inhibits the internalisation of AMPAR.