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Orexin-A Augments Voltage-Gated Ca²⁺ Currents and Synergistically Increases Growth Hormone (GH) Secretion with GH-Releasing Hormone in Primary Cultured Ovine Somatotropes

Prince Henry’s Institute of Medical Research (R.X., Q.W., M.Y., M.H., C.G., W.C.B., Y.M., C.C.), Clayton, Victoria 3168, Australia; Department of Physiology, Monash University (R.X., C.C.), Clayton, Victoria 3168, Australia; and Department of Physiology, University of Occupational and Environmental Health (Y.U.), Yahatanishi-ku, 807-8555, Kitakyushu, Japan

Address all correspondence and requests for reprints to: Dr. Chen Chen, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: chen.chen{at}med.monash.edu.au.

Orexins are recently discovered neuropeptides that play an important role in the regulation of hormone secretion, and their receptors have been recently demonstrated in the pituitary. The effects of orexin-A on voltage-gated Ca²⁺ currents and GH release in primary cultured ovine somatotropes were examined. The expression of orexin-1 receptor was demonstrated by RT-PCR in ovine somatotropes, from which Ca²⁺ currents were also isolated as L, T, and N currents. Application of orexin-A (100 nM) significantly and reversibly increased only the L current, and coadministration of orexin-A and GHRH (10 nM) showed an additive effect on this current, but no effect of orexin-A was observed on either T or N current. Furthermore, the orexin-A-induced increase in the L current was completely abolished by the inhibition of protein kinase C (PKC) activity using calphostin C (100 nM), phorbal 12,13-dibutyrate pretreatment (0.5 µM) for 16 h or specific PKC inhibitory peptide PKC_19–36 (1 mM). However, the increase in L current by orexin-A was sustained when cells were preincubated with a specific protein kinase A blocker H89 (1 µM) or a specific intracellular Ca²⁺ store depleting reagent thapsigargin (1 µM). Finally, orexin-A alone did not significantly increase GH release, but coadministration of orexin-A and GHRH showed a synergistic effect on GH secretion in vitro. Our results therefore suggest that orexin-A may play an important role in regulating GHRH-stimulated GH secretion through the enhancement of the L-type Ca²⁺ current and the PKC-mediated signaling pathway in ovine somatotropes.

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