Proline-Rich Motifs and Immune-Brain Loop Communication
Having read the brilliant article entitled "The Scaffolding Protein Synapse-Associated Protein 97 Is Required for Enhanced Signaling Through Isotype-Switched IgG Memory B Cell Receptors " by Wanli Liu et al. (1), about a mechanism by which the PDZ (postsynaptic density 95/disc large/zona occludens 1) domain of scaffolding protein SAP97 interacts with the IgG (immunoglobulin G) BCR (B cell receptor) at the memory B cell immunological synapse, I would like to discuss possible functional similarities between immunological and neurological synapses.
We belong to a team investigating the communication between the immune and nervous systems, the immune-brain loop. More specifically, we study the action of antipsychotic drugs on acquired and innate immunity by studying the influence of pharmacological treatment on plasma concentrations of immunoglobulins (Igs), the C3 and C4 components of the complement system, and other cytokines.
We evaluated a study reporting the 100 SNPs (single nucleotide polymorphisms) most closely associated with disease in schizophrenic patients (SCH) (2), leading us to conclude that these polymorphisms affect proline-containing peptidic sequences present in different protein isoforms (3). We know that plasma concentrations of the different types of Igs are altered in SCH and, in turn, the abundance of these Ig molecules are modified by the antipsychotic treatment, which may act directly to block or activate one or more neurotransmitter receptors, such as dopamine and serotonin receptors, that are located in the membrane of B cells, or may act indirectly by altering the release of neurotransmitters from neurons. Because B cells produce both neurotransitters and Igs, the membrane of B cells may be one of several places where the immune and nervous systems converge.
The abundance of the postsynaptic protein PSD95 is increased in neurological synapses of SCH patients. According to the results in the paper by Liu et al., the clustering of receptors in the immunological synapse of memory B cells is altered by the scaffolding actions of the PDZ domain of SAP97, which also functions in neuronal synapses at a site of receptor clustering called the postsynaptic density (PSD) and is related to PSD95.
SAP97, like many other PDZ domain–containing proteins (such as PSD95), also contains an SH3 domain, which mediates protein-protein interactions by binding to proline-rich sequences (X-P-P-X-P). Therefore, it seems reasonable to wonder whether proline-rich motifs present in proteins of the neurological and immunological synapses bind similar proteins in the immune and nervous systems and could be one of the links between the immune and nervous systems.
Secondly, is the internalization of proteins, with PDZ-binding domains or proline-rich motifs, that can associate with the PSD in neurological synapses and sites of receptor clustering at immunological synapses, a mechanism for regulation of the abundance of these interacting proteins?
1. W. Liu, E. Chen, X. W. Zhao, Z. P. Wan, Y. R. Gao, A. Davey, E. Huang, L. Zhang, J. Crocetti, G. Sandoval, M. G. Joyce, C. Miceli, J. Lukszo, L. Aravind, W. Swat, J. Brzostowski, S. K. Pierce, The scaffolding protein synapse-associated protein 97 is required for enhanced signaling through isotype-switched IgG memory B cell receptors Sci. Signal. 5, ra54 (2012).
2. A.C. Need, D. Ge, M.E. Weale, J. Maia, S. Feng E.L. Heinzen, K.V. Shianna, W. Yoon , D. Kasperaviciūte, M. Gennarelli , W.J. Strittmatter , C. Bonvicini, G. Rossi, K. Jayathilake , P.A. Cola , J.P. McEvoy, R.S. Keefe, E.M. Fisher, P.L. St Jean, I. Giegling, A.M. Hartmann, H.J. Möller, A. Ruppert, G. Fraser, C. Crombie, L.T. Middleton, D. St Clair, A.D. Roses, P. Muglia, C. Francks, D. Rujescu, H.Y. Meltzer, D.B. Goldstein, A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet. 5, e1000373 (2009). doi:10.1371/journal.pgen.1000373
3. R. Lozano, R. Marin, I. Freire, F. Sebastian, M. J. Santacruz, A. Velilla Schizophrenia: Influence of single nucleotide polymorphisms on peptidic sequence. XXV Congress of Spanish Society of Clinical Pharmacology (2012).
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