Key Role of the Postsynaptic Density Scaffold Proteins Shank and Homer in the Functional Architecture of Ca²⁺Homeostasis at Dendritic Spines in Hippocampal Neurons

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…The EVH1 domain exhibits a high degree of similarity across Homer isoforms and is essential for Homer interactions with a proline-rich sequence (PPSPF) displayed by proteins regulating drug-induced alterations in neuronal morphology, synaptic architecture, and glutamate receptor signaling/intracellular calcium dynamics. Of particular relevance to drug-induced neuroplasticity [e.g., 20,73,74,[78][79][80][81][82][89][90][91][92][93][94][95][96][97][98][99][100][123][124][125][126][127][128][129][130], these proteins include the mGluR1a and mGluR5 subtypes of Group 1 metabotropic glutamate receptors (mGluRs) [34,102,104,107,[131][132][133][134][135][136][137], the NMDA glutamate receptor scaffolding protein Shank [38,132,138,139], the inositol-1,4,5-triphosphate (IP3) receptor, a down-stream mediator of Group1 mGluR signaling [133,[140]…”

“…The co-transfection of Homer1b with Shank1b in developing hippocampal neuronal cultures induces the maturation of spines and causes an enlargement in dendritic spine size, compared to the transfection of either protein alone [140,145;172]. Moreover, co-transfection of Homer1b with Shank1b also recruits IP3Rs and endoplasmic cisternae to the PSD [140,172]. The maturation and enlargement of spines requires the physical interaction of Homer and Shank as co-transfection of Homer1b with a mutant form of Shank that is incapable of binding Homer or the co-transfection of Shank1b with the truncated Homer1a did not alter spine size or shape [140,172].…”

“…Moreover, co-transfection of Homer1b with Shank1b also recruits IP3Rs and endoplasmic cisternae to the PSD [140,172]. The maturation and enlargement of spines requires the physical interaction of Homer and Shank as co-transfection of Homer1b with a mutant form of Shank that is incapable of binding Homer or the co-transfection of Shank1b with the truncated Homer1a did not alter spine size or shape [140,172]. Within the PSD, CC-Homer proteins colocalize with F-actin/Shank/PSD-95/ GKAP/NMDA receptor clusters [132,147].…”

“…Within the PSD, CC-Homer proteins colocalize with F-actin/Shank/PSD-95/ GKAP/NMDA receptor clusters [132,147]. Corresponding to the maturation and enlargement of dendritic spines by Homer-Shank interactions [e.g., 145] is the recruitment of the NR2b subunit of the NMDA receptor, as well as, a number of other scaffolding and signaling molecules associated with glutamate receptors, including GKAP, PSD-95, IP3Rs, F-actin and various proteins related to the endoplasmic reticulum cisterna [132,140,[145][146][147]151,172]. In mature neurons, the distribution and clustering of CC-Homers within dendritic spines is regulated by neuronal activity.…”

Rho-linked genes and neurological disorders

“…Moreover, Homer proteins have been shown to influence dendritic spine morphogenesis and synaptic transmission [26,71,72]. Although the function of OPHN1/Homer interaction remains to be established, it raises the intriguing possibility that OPHN1 provides a crucial link between postsynaptic receptors (via Homer) and the actin cytoskeleton to regulate dendritic spine morphogenesis and synaptic function.…”