#Protein scaffold interaction Activator#

These models can be effectively leveraged by drawing on concepts from the National Institute of Mental Health Research Domain Criteria (RDoC) Initiative, which aims to delineate molecular pathways and neural circuits that underpin behavioral anomalies that transcend psychiatric conditions. Overall, while confirming a key role of glutamatergic synapse in the molecular pathophysiology of schizophrenia, we reported molecular signatures encompassing elements of the glutamate synapse able to discriminate patients with schizophrenia and normal individuals.Īnimal models provide important tools to study biological and environmental factors that shape brain function and behavior. Furthermore, a Machine Learning hypothesis-free unveiled other discriminative clusters of molecules, one in the DLPFC and another in the hippocampus. Nonetheless, multivariable hypothesis-driven analyses revealed that the presence of schizophrenia was significantly affected by variations in neuroactive amino acid levels and glutamate-related synaptic elements. Univariable analyses revealed that none of the investigated molecules was differently represented in the post-mortem DLPFC and hippocampus of schizophrenia patients, compared with controls. Moreover, by quantitative RT-PCR and western blotting we analyzed, respectively, the mRNA and protein levels of pre- and post-synaptic key molecules involved in the glutamatergic synapse functioning, including glutamate receptors (NMDA, AMPA, metabotropic), their interacting scaffolding proteins (PSD-95, Homer1b/c), plasma membrane and vesicular glutamate transporters (EAAT1, EAAT2, VGluT1, VGluT2), enzymes involved either in glutamate-dependent GABA neurotransmitter synthesis (GAD65 and 67), or in post-synaptic NMDA receptor-mediated signaling (CAMKIIα) and the pre-synaptic marker Synapsin-1. We investigated in the post-mortem dorsolateral prefrontal cortex (DLPFC) and hippocampus of schizophrenia patients and non-psychiatric controls, the levels of neuroactive d- and l-amino acids (l-glutamate, d-serine, glycine, l-aspartate, d-aspartate) by HPLC. However, a multi-level approach tackling diverse clusters of interacting molecules of the glutamate signaling in schizophrenia is still lacking. IP3 binds to intracellular IP3 receptors (IP3R) on the endoplasmic reticulum (ER) membrane initiating Ca2+ release from the ER lumen into the cytoplasm, generating complex Ca2+ concentration-dependent signals, including temporal oscillations, and propagating waves.Ībstract Schizophrenia is a disorder of synaptic plasticity and aberrant connectivity in which a major dysfunction in glutamate synapse has been suggested.

#Protein scaffold interaction Activator#

DAG is the physiological activator of protein kinase C (PKC), which in turn activates various intracellular signaling cascades. Activation of PLC results in the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) to release the second messengers 1,2-Diacylglycerol (DAG) and IP3. mGluR5 activation by glutamate initiates Gq protein signaling that regulates the function of phospholipase C (PLC). Homer interactions with mGluR5 are further regulated by Preso1 scaffolding proteins. Homer proteins form multimers through interactions of their coiled-coil domain and link Shank to mGluR5 and inositol triphosphate (IP3) or ryanodine receptors. The proline rich domain of Shank interacts with the EVH domain of Homer proteins. The PDZ domain of Shank interacts with the c terminus of guanylate kinase-associated protein (GKAP), which is in turn associated with the ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor-PSD95 complex. The SH3-multiple ankyrin domain-containing protein (Shank) is a prototypical PDZ scaffolding protein. Interaction of mGluR5 with scaffolding proteins and signaling molecules.