Ca2+ Signaling Enables Growth Hormone Secretion from Cultured Mice Pituitary Somatotrophs, Facilitating Outgrowth in Hypothalamic Neuron

  • Neurochem Res. 2026 Apr 21;51(3):144. doi: 10.1007/s11064-026-04755-1.
Samuel Shin  1  2 ,  Samshritha Bikki  1  2 ,  Kimberly Byrnes  3 ,  Bidhan C Bandyopadhyay  4  5  6
Affiliations
  • 1. Veterans Affairs Medical Center, Research Service, 50 Irving Street, NW, Washington, DC, 20422, USA.
  • 2. Department of Biomedical Engineering, The Catholic University of America, 620 Michigan Avenue NE, Washington, DC, 20064, USA.
  • 3. Department of Anatomy, Physiology and Genetics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
  • 4. Veterans Affairs Medical Center, Research Service, 50 Irving Street, NW, Washington, DC, 20422, USA. [email protected].
  • 5. Department of Biomedical Engineering, The Catholic University of America, 620 Michigan Avenue NE, Washington, DC, 20064, USA. [email protected].
  • 6. Calcium Signaling Laboratory, 151 Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC, 20422, USA. [email protected].
PMID: 42012561 DOI: 10.1007/s11064-026-04755-1
Abstract

The hypothalamus regulates anterior pituitary (AP) hormone release via the hypophyseal portal system by secreting specific releasing and inhibiting peptide Hormones. Growth hormone (GH) secretion from pituitary somatotrophs (PS) is regulated by a cholinergic mechanism that induces calcium (Ca2+) signaling, which in turn triggers vesicular exocytosis and GH release. Given that the transient receptor potential canonical channel 3 (TRPC3) regulates vesicle exocytosis in endocrine and neuroendocrine cells, we investigated its role in GH release from somatotrophs and whether GH release could support neuronal growth in the hypothalamus. Activation of TRPC3 by the diacylglycerol analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), resulted in a rapid increase in intracellular Ca2+ ([Ca2+]i) in wild type (WT) PS, attenuated by the TRPC3 inhibitor Pyr10, or by the knockout of TRPC3. ELISA assay confirmed that OAG exposure triggered GH release in WT PS. Conditioned media from OAG-stimulated PS promoted significant neurite outgrowth in hypothalamic neuronal cultures, suggesting a role for released GH in this process. Exposure of PS to H2O2-induced oxidative damage enhanced store-operated Ca2+ entry (SOCE) compared to control cells. Electrophysiological characterization revealed that somatotrophs under increased Reactive Oxygen Species (ROS) conditions exhibited elevated SOCE, whereas cells under more native conditions exhibited receptor-operated Ca2+ entry. Furthermore, media from oxidative-stressed PS cultures, followed by the OAG exposure, induced neurite outgrowth, suggesting TRPC3 activation may provide an alternative pathway after ROS-induced damage in GH release. These findings indicate that Ca2+ signaling activation may promote GH secretion from control and ROS-induced AP cells, potentially leading to neurite outgrowth in hypothalamic cells. This study may provide insights into restoring neuronal connectivity following brain injury.

Keywords
Anterior pituitary; Ca2+ signaling; Growth hormone; Hypothalamus; Neuronal growth; Oxidative stress.
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