The Neuregulin System of Ligands and Their Receptors in Rat Islets of Langerhans

Islet cell growth and function are affected by ligands from the epidermal growth factor (EGF) family. We describe here the expression, regional distribution, and effect on growth and secretion of insulin of a subset of these, the neuregulin (NRG) family. The expression of NRG1α, NRG1β, NRG2α, NRG2β, NRG3, and NRG4 in rat islets was determined using immunohistochemical and double immunofluorescent staining. We also report the expression of the 4 receptors and the remaining 7 ligands using immunohistochemistry. The NRG1α splice variant was expressed in β-cells and the NRG1β variant mainly in α-cells. NRG3 was also predominantly present in α-cells. Most of the members of the EGF family of ligands were also expressed, with Epigen being present at the highest levels. The rat islet-derived cell line CRI-G1 was used to study the effect of addition of EGF, NRG1β, NRG3, and NRG4 on cell growth and insulin secretion. Synthetic refolded NRG3 strongly stimulated the growth of the CRI-G1 cells, and NRG4 gave the greatest stimulation of insulin release. Different members of the NRG family are therefore potentially potent stimuli for islet cell growth and insulin release and differ in expression in α- and β-cells.