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Received for publication May 27, 2005.
Revised October 28, 2005.
Accepted for publication October 28, 2005.
INDUCES PROLIFERATION AND GROWTH HORMONE RELEASE IN GH4C1 RAT PITUITARY ADENOMA CELL LINE, THROUGH MULTIPLE INTRACELLULAR SIGNALS
We used GH4C1 cells as a model to study the effects of the chemokine SDF1 in pituitary functions. In these cells, SDF1
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, SDF1 increased cytosolic [Ca2+] and activated Pyk2, ERK1/2 and BKCa channels. To correlate these intracellular effectors with the proliferative and secretory effects, we inhibited their activity using BAPTA-AM (Ca2+ chelator), PD98059 (MEK inhibitor), salicylate (Pyk2 inhibitor) and TEA (K+ channel blocker). All these compounds reverted SDF1-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 SDF1 dependent activation of ERK1/2, Pyk2 and BKCa channels. From these experiments we observed that: the inhibition of [Ca2+]i increase or BKCa channels activity did not affect ERK1/2 activation by SDF1; Pyk2 activation was purely Ca2+ dependent, not involving ERK1/2 or BKCa channels; BKCa channels activity was antagonized by Pyk2 but not by ERK1/2 inhibitors. These data suggest that SDF1-dependent increase of [Ca2+]i activates Pyk2, that, in turn, regulates BKCa channel activity. Conversely, ERK1/2 activation is an independent phenomenon. In conclusion we demonstrate that SDF1 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, that may contribute to pituitary adenoma development.
Key words:
Neuropeptides, Growth hormone, G protein regulation, MAP Kinase, Ca imaging
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