Latrophilin GPCR signaling mediates synapse formation
Richard Sando1, Thomas C Südhof1
1Department of Molecular & Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, United States.
Elife
|March 1, 2021
Summary
Latrophilins are crucial for brain synapse formation. These G protein-coupled receptors (GPCRs) require signaling activity to establish new neural connections in the hippocampus.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Neural circuit assembly relies on precise synaptic connections, but the underlying mechanisms are not fully understood.
- Latrophilins, a family of adhesion G protein-coupled receptors (GPCRs), form trans-synaptic complexes with presynaptic teneurins and FLRTs.
- Latrophilin-2 and Latrophilin-3 are vital for forming specific synapses in mouse hippocampal CA1 neurons.
Purpose of the Study:
- To investigate whether latrophilins function as GPCRs in the process of synapse formation.
- To elucidate the role of GPCR signaling in latrophilin-mediated synapse assembly.
Main Methods:
- Examined the constitutive GPCR activity of Latrophilin-2 and Latrophilin-3 by measuring cAMP levels.
- Utilized a mutation that disrupts G-protein and arrestin interactions to assess the functional requirement of GPCR signaling.
- Assessed the ability of Latrophilin-2 and Latrophilin-3 to rescue synapse loss in knockout neurons in vivo.
Main Results:
- Latrophilin-2 and Latrophilin-3 demonstrated constitutive GPCR activity, leading to increased cAMP levels.
- A mutation impairing GPCR interactions abolished the ability of latrophilins to increase cAMP.
- The same mutation prevented Latrophilin-2 and Latrophilin-3 from rescuing the synapse-loss phenotype in knockout mice.
Conclusions:
- Latrophilin-2 and Latrophilin-3 necessitate GPCR signaling for their role in synapse formation.
- Latrophilins promote hippocampal synapse assembly by activating canonical GPCR signaling pathways.
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