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The binding of Nrg1 to ErbB receptors mediates intercellular and intracellular communication, and it regulates a broad spectrum of biological processes, such as tumorigenesis and myelination.Recombinant Nrg1 has been shown to control prolactin (PRL) secretion from rat prolactinoma GH3 cells.However, the endogenous expression of Nrg1 and its role in PRL secretion in GH3 cells are not known.In this study, we demonstrate that type Ⅲ Nrg1 isoforms are endogenously expressed in GH3 cells.An in vitro functional analysis using siRNA against Nrg1 revealed that endogenous Nrg1 regulates PRL secretion from GH3 cells in part through an ErbB-3 receptor-dependent manner, with no significant effects on growth hormone (GH) secretion.Therefore, Nrgl is a specific modulator of PRL secretion in GH3 cells.Additionally, co-localization of Nrg1 and ErbB-2 receptor, which is shared by both ErbB-3 and ErbB-4 receptors in the formation of heterodimers, was detected in one out of 5 human prolactinoma tissues.Our findings suggest that GH3 cells intrinsically express a group of type Ⅲ Nrg1 isoforms that regulate PRL secretion through an autocrine/paracrine mechanism.Further investigation into the role of Nrg1 on PRL secretion may provide clues to advance the clinical management of prolactinoma.