We used GH4C1 cells as a model to study the effects of the chemokine stromal cell-derived factor 1 (SDF1) in pituitary functions. In these cells, SDF1α induced proliferation and growth hormone secretion, suggesting a possible regulatory role for this chemokine at pituitary level. We evaluated the intracellular signaling involved in these effects: SDF1α increased cytosolic [Ca2+] and activated Pyk2, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and large-conductance Ca2+-activated K + channels (BKCa) channels. To correlate these intracellular effectors with the proliferative and secretory effects, we inhibited their activity using BAPTA-AM (Ca2+ chelator), 2′-amino-3′-methoxyflavone (PD98059; a mitogen-activated protein kinase kinase inhibitor), salicylate (Pyk2 inhibitor), and tetraethyl ammonium (K+ channel blocker). All of these compounds reverted SDF1α-induced proliferation, suggesting the involvement of multiple intracellular pathways. Conversely, only BAPTA-AM reverted growth hormone secretion. To identify a possible cross-talk and a molecular ordering among these pathways, we tested these antagonists on SDF1α-dependent activation of ERK1/2, Pyk2, and BKCa channels. From these experiments, we observed that the inhibition of [Ca2+]i increase or BKCa channel activity did not affect ERK1/2 activation by SDF1α; Pyk2 activation was purely Ca2+-dependent, not involving ERK1/2 or BKCa channels; and BKCa channel activity was antagonized by Pyk2 but not by ERK1/2 inhibitors. These data suggest that an SDF1α-dependent increase of [Ca2+]i activates Pyk2, which in turn regulates BKCa channel activity. Conversely, ERK1/2 activation is an independent phenomenon. In conclusion, we demonstrate that SDF1α causes both proliferation and growth hormone release from pituitary adenoma cells, suggesting that the activation of CXCR4 may represent a novel regulatory mechanism for growth hormone secretion and pituitary cell proliferation, which may contribute to pituitary adenoma development.
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