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Hierarchical organization and genetically separable subfamilies of PSD 95 postsynaptic supercomplexes
Author(s) -
Frank René A. W.,
Zhu Fei,
Komiyama Noboru H,
Grant Seth G. N.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14056
Subject(s) - biology , postsynaptic density , neurotransmitter receptor , postsynaptic potential , population , ion channel , microbiology and biotechnology , biochemistry , receptor , demography , sociology
PSD 95 is an abundant postsynaptic scaffold protein in glutamatergic synapses that assembles into supercomplexes composed of over 80 proteins including neurotransmitter receptors, ion channels and adhesion proteins. How these diverse constituents are organized into PSD 95 supercomplexes in vivo is poorly understood. Here, we dissected the supercomplexes in mice combining endogenous gene‐tagging, targeted mutations and quantitative biochemical assays. Generating compound heterozygous mice with two different gene‐tags, one on each Psd95 allele, showed that each ~1.5 MD a PSD 95‐containing supercomplex contains on average two PSD 95 molecules. Gene‐tagging the endogenous GluN1 and PSD 95 with identical Flag tags revealed N‐methyl D‐aspartic acid receptors ( NMDAR s) containing supercomplexes that represent only 3% of the total population of PSD 95 supercomplexes, suggesting there are many other subtypes. To determine whether this extended population of different PSD 95 supercomplexes use genetically defined mechanisms to specify their assembly, we tested the effect of five targeted mouse mutations on the assembly of known PSD 95 interactors, Kir2.3, Arc, IQ sec2/ BRAG 1 and Adam22. Unexpectedly, some mutations were highly selective, whereas others caused widespread disruption, indicating that PSD 95 interacting proteins are organized hierarchically into distinct subfamilies of ~1.5 MD a supercomplexes, including a subpopulation of Kir2.3‐ NMDAR ion channel‐channel supercomplexes. Kir2.3‐ NMDAR ion channel‐channel supercomplexes were found to be anatomically restricted to particular brain regions. These data provide new insight into the mechanisms that govern the constituents of postsynaptic supercomplexes and the diversity of synapse types. Read the Editorial Highlight for this article on page 500. Cover Image for this issue: doi. 10.1111/jnc.13811 .