FIGURE 2.

Interplay between metabotropic receptors and extracellular matrix in homeostatic plasticity. (1) Network activity and neuromodulatory systems stimulate G protein-coupled receptors (GPCRs) [metabotropic glutamate receptors 1/5 (mGluR1/5), D1/5 dopamine receptors, 5-HT7R serotonin receptors] and (2) downstream signaling networks [including calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), protein kinase C (PKC), and inositol trisphosphate receptors (IP₃Rs)]. (3) This results in activation of extracellular proteinases [tumor necrosis factor-α-converting enzyme (TACE), disintegrin and metalloprotease with thrombospondin motifs 4/5 (ADAMTS4/5), matrix metalloproteinase 9 (MMP9)], which (4) may process ECM molecules (lecticans) or (5) ECM receptors (NPR, CD44), enabling synaptic modifications (not shown) as well as (6) signaling back through modulation of GPCRs (group III mGluR) and (7) additional intracellular signaling events. (8) Inactivity increases cell surface expression and signaling through major extracellular matrix (ECM) receptors, β3 integrins. (9) Activity stimulates secretion of Narp and its coaggregation with GluAs on interneurons. (10) Intracellular signaling cascades are converging on regulation of trafficking of GluAs [homeostatic synaptic plasticity (HSP)] or voltage- and Ca²⁺-gated ion channels (HIP).