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Ca²⁺ Mobilization, Tyrosine Hydroxylase Activity, and Signaling Mechanisms in Cultured Porcine Adrenal Medullary Chromaffin Cells: Effects of Leptin¹

Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

Address all correspondence and requests for reprints to: Kazuhiro Takekoshi, Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba 1–1-1 Tennoudai, Tsukuba, 305-8575, Japan.

Leptin acts as a satiety factor, but there is also evidence that it affects energy expenditure. Leptin’s effects are mediated by its receptors, which function as activators of a Janus family of tyrosine kinases-signal transducer and activator of transcription (JAK-STAT) pathway. We have previously shown that murine recombinant leptin markedly induces both the release of catecholamine and tyrosine hydroxylase (TH) (rate-limiting enzyme in the biosynthesis of catecholamine)-messenger RNA (mRNA) levels, probably through Ob-Rb expressed in cultured porcine chromaffin cells. In the present study, we examined the effect of leptin on Ca²⁺ mobilization, TH enzyme activity, and signaling. Ca²⁺ channel blockers, nicardipine and -Conotoxin GVIA, each at 1 µM, were effective in inhibiting leptin-induced catecholamine secretion. When intracellular Ca²⁺ ([Ca²⁺]_i) was measured in fura 2-loaded chromaffin cells, leptin was found to cause a sustained increase of Ca²⁺ by mobilizing Ca²⁺ from both extra- and intracellular pools. Additionally, leptin significantly stimulated inositol 1.4.5-triphosphate IP₃ production in a dose-dependent manner. TH-activity is regulated by both TH enzyme activity and increased TH-mRNA levels accompanied by increased TH protein synthesis. Leptin (1 nM) significantly stimulated TH enzyme activity and increased the TH protein level, indicating that it stimulates catecholamine biosynthesis. In addition, removal of external Ca²⁺ completely inhibited leptin (100 nM)-induced TH enzyme activity. Leptin (1 nM) caused an increase in the activity of mitogen-activated protein kinases (MAPKs) that was accompanied by increased phosphorylation of STAT-3 and -5, but not STAT-1. Moreover, MAPK activity evoked by leptin(100 nM) and TH-mRNA caused by leptin (10 nM) were inhibited by 50 and 30 µM of PD-98059 (the MAP kinase kinase-1 inhibitor), respectively. These findings indicate that leptin activates voltage-dependent Ca²⁺ channels (VDCC), presumably L-type and N-type Ca²⁺ channels, as well as phospholipase C, and suggest that leptin-induced catecholamine secretion is mainly mediated by activation of VDCC. In addition, leptin stimulates the JAK-STAT pathway as well as increasing the levels of TH-mRNA levels through the MAPK pathway in porcine chromaffin cells.

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