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- W4242373885 abstract "Glucagon is secreted from pancreatic islet alpha-cells in response to hypoglycemia. The regulation of this secretion remains poorly understood even after 40 years of research, but it likely involves multiple interacting molecular pathways. Proposed models for glucose-dependent regulation of glucagon secretion fall into three general types: direct regulation by glucose, paracrine regulation by other cell types within the islets of Langerhans, and juxtacrine regulation by the neighboring beta-cells. This work is focused on one pathway of juxtacrine regulation that occurs through interactions of ephrin-A5 ligands on the surface of beta-cells and EphA4 receptors on the alpha-cells. In this pathway, stimulation of EphA4 leads to dense F-actin network that inhibits the secretion of glucagon vesicles. However, the molecular pathway downstream of EphA4 is poorly understood. We present evidence that RhoA, a Rho family GTPase, links EphA4 stimulation to F-actin polymerization and formation of more dense cortical actin networks. Pharmacological inhibition of RhoA resulted in the disruption of proper glucose-inhibition of glucagon secretion and correlated to a loss of F-actin network density. Quantitative imaging measurements using a FRET biosensor for RhoA activity showed that EphA4 stimulation increase RhoA activity. Using a fluorescent nanobody for F-actin, we could also show that the dynamics of RhoA and F-actin formation are correlated following EphA4 stimulation. Further, quantitative imaging showed that glucose-dependent changes in RhoA activity and F-actin polymerization are independent from intracellular Ca2+ activity. These results implicate RhoA as the key regulator of F-actin in the ephrin-A5-EphA4 juxtacrine regulation pathway." @default.
- W4242373885 created "2022-05-12" @default.
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- W4242373885 date "2020-02-01" @default.
- W4242373885 modified "2023-09-28" @default.
- W4242373885 title "RhoA Mediated Juxtacrine Regulation of Glucagon Secretion" @default.
- W4242373885 doi "https://doi.org/10.1016/j.bpj.2019.11.1454" @default.
- W4242373885 hasPublicationYear "2020" @default.
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