Agosto lab
Vision begins in the retina with rod and cone photoreceptor cells. These specialized neurons detect photons, then relay information via synaptic transmission to downstream neurons called bipolar cells. Proper formation and function of the synapses between photoreceptors and bipolar cells requires multiple specific proteins on both presynaptic and postsynaptic membranes. The long-term goals of our research are to understand how proteins are targeted and delivered to the synapse, how they assemble and function together, and how synapse formation is regulated. Understanding these retinal circuits at the molecular level is crucial for understanding normal vision. Furthermore, this work will help future efforts to restore light sensitivity following the death of rods and cones that occurs in inherited retinal degeneration diseases.
Research areas
- Retinal neurobiology
- Synaptic trafficking
- Macromolecular protein complexes
- G-protein coupled receptors
- Signal transduction
Current projects
1. Trafficking of metabotropic glutamate receptors. At ON-type bipolar cells, the neurotransmitter is detected by a metabotropic glutamate receptor, mGluR6. Other members of the mGluR family are found throughout the central nervous system. We are investigating mechanisms of mGluR secretory trafficking and synaptic targeting in cultured cells and retina tissue.
2. Assembly of synaptic complexes. At photoreceptor-bipolar cell synapses, trans-synaptic complexes containing both pre- and post-synaptic proteins are necessary for synapse formation and function. One aim of our research program is to characterize protein-protein interactions in the synaptic cleft.
3. Characterization of patient mutations in synaptic proteins. Congenital stationary night blindness (CSNB) is caused by defects in synaptic transmission from photoreceptors to bipolar cells, and mutations in a number of synaptic proteins have been associated with CSNB. We are characterizing the functional consequences of these mutations.
Selected publications
Miller ML, Pindwarawala M, Agosto MA. 2024. Complex N-glycosylation of mGluR6 is required for trans-synaptic interaction with ELFN adhesion proteins. The Journal of Biological Chemistry, in press.
Haggerty KN, Eshelman SC, Sexton LA, Frimpong E, Rogers LM, Agosto MA, Robichaux MA. 2024. Super-resolution mapping in rod photoreceptors identifies rhodopsin trafficking through the inner segment plasma membrane as an essential subcellular pathway. PLoS Biology 22, e3002467.
Zhang Z, Moye A, He F, Chen Muyuan, Agosto MA, Wensel TG. 2024. Centriole and transition zone structures in photoreceptor cilia revealed by cryo-electron tomography. Life Science Alliance 7, e202302409.
Huh E, Agosto MA, Wensel TG, Lichtarge O. 2023. Co-evolutionary signals in metabotropic glutamate receptors capture residue contacts and long-range functional interactions. The Journal of Biological Chemistry 299, 103030.
Agosto MA, Adeosun AA, Kumar N, Wensel TG. 2021. The mGluR6 ligand-binding domain, but not the C-terminal domain, is required for synaptic localization in retinal ON-bipolar cells. Journal of Biological Chemistry 297: 101418.
Huh E, Gallion J, Agosto MA, Wright SJ, Wensel TG, Lichtarge O. 2021. Recurrent high-impact mutations at cognate structural positions in Class A GPCRs expressed in tumors. Proceedings of the National Academy of Sciences USA 118, e2113373118.
Agosto MA, Wensel TG. 2021. LRRTM4 is a member of the transsynaptic complex between rod photoreceptors and ON bipolar cells. Journal of Comparative Neurology 529, 221-233.
He F, Nichols RM, Kailasam L, Wensel TG, Agosto MA. 2019. Critical role for phosphatidylinositol-3 kinase Vps34/PIK3C3 in ON-bipolar cells. Investigative Ophthalmology & Visual Science 60, 2861-2874.
Agosto MA, Anastassov IA, Wensel TG. 2018. Differential epitope masking reveals synapse-specific complexes of TRPM1. Visual Neuroscience 35, E001.
Agosto MA, Anastassov IA, Robichaux MA, Wensel TG. 2018. A large endoplasmic reticulum-resident pool of TRPM1 in retinal ON bipolar cells. eNeuro 5, ENEURO.0143-18.2018.
He F, Agosto MA, Anastassov IA, Tse DY, Wu SM, Wensel TG. 2016. Phosphatidylinositol-3-phosphate is light-regulated and essential for survival in retinal rods. Scientific Reports 6, 26978.
Zhang Z, He F, Constantine R, Baker ML, Baehr W, Schmid MF, Wensel TG, Agosto MA. 2015. Domain organization and conformational plasticity of the G protein effector, PDE6. The Journal of Biological Chemistry 290, 12833-12843.
Agosto MA, Zhang Z, He F, Anastassov IA, Wright SJ, McGehee J, Wensel TG. 2014. Oligomeric state of purified transient receptor potential melastatin-1 (TRPM1), a protein essential for dim light vision. Journal of Biological Chemistry 289, 27019-27033.