Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk

Cellular signaling involves a large repertoire of membrane receptors operating in overlapping spatiotemporal regimes and targeting many common intracellular effectors. However, both the molecular mechanisms and the physiological roles of crosstalk between receptors, especially those from different superfamilies, are poorly understood. We find that the receptor tyrosine kinase (RTK) TrkB and the G-protein-coupled receptor (GPCR) metabotropic glutamate receptor 5 (mGluR5) together mediate hippocampal synaptic plasticity in response to brain-derived neurotrophic factor (BDNF). Activated TrkB enhances constitutive mGluR5 activity to initiate a mode switch that drives BDNF-dependent sustained, oscillatory Ca2+ signaling and enhanced MAP kinase activation. This crosstalk is mediated, in part, by synergy between Gβγ, released by TrkB, and Gαq-GTP, released by mGluR5, to enable physiologically relevant RTK/GPCR crosstalk. [Display omitted] •BDNF-driven synaptic plasticity is dependent on mGluR5•mGluR5 enables a mode switch in BDNF-TrkB signaling•Non-canonical G-protein coupling drives BDNF-induced plasticity•G-protein-dependent crosstalk is seen between multiple RTKs and Gq-coupled GPCRs Lao-Peregrin et al. find that BDNF-driven hippocampal synaptic plasticity is dependent on functional crosstalk with mGluR5. Mechanistic studies reveal a general mode of RTK/GPCR crosstalk that is driven by G-protein synergy.