The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

The TRPC1 (transient receptor potential canonical-1) channel is a constituent of the nonselective cation channel that mediates Ca²⁺ entry through store-operated channels (SOCs) in human endothelial cells. We investigated the role of protein kinase Cα (PKCα) phosphorylation of TRPC1 in regulating the opening of SOCs. Thrombin or thapsigargin added to the external medium activated Ca²⁺ entry after Ca²⁺ store depletion, which we monitored by changes in cellular Fura 2 fluorescence. Internal application of the metabolism-resistant analog of inositol 1,4,5-trisphosphate (IP₃) activated an inward cationic current within 1 min, which we recorded using the whole cell patch clamp technique. La³⁺ or Gd³⁺ abolished the current, consistent with the known properties of SOCs. Pharmacological (Gö6976) or genetic (kinase-defective mutant) inhibition of PKCα markedly inhibited IP₃-induced activation of the current. Thrombin or thapsigargin also activated La³⁺-sensitive Ca²⁺ entry in a PKCα-dependent manner. We determined the effects of a specific antibody directed against an extracellular epitope of TRPC1 to address the functional importance of TRPC1. External application of the antibody blocked thrombin- or IP₃-induced Ca²⁺ entry. In tion, we showed that addithrombin or thapsigargin induced phosphorylation of TRPC1 within 1 min. Thrombin failed to induce TRPC1 phosphorylation in the absence of PKCα activation. Phosphorylation of TRPC1 and the resulting Ca²⁺ entry were essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. These results demonstrate that PKCα phosphorylation of TRPC1 is an important determinant of Ca²⁺ entry in human endothelial cells.

Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1α. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1α activity in tumors. Pheochromocytomas (also known as paragangliomas) are highly vascular tumors that arise from mutations in a diverse and apparently unrelated group of tumor suppressor genes and oncogenes. The authors show here that three of the genes that cause hereditary pheochromocytomas have a common function. Specifically, these genes, VHL, SDHB, and SDHD, encode proteins that regulate a transcription factor known as hypoxia-inducible factor 1 subunit α (HIF1α), which helps cells adapt to hypoxia (low oxygen levels). VHL is named after its role in von Hippel-Lindau disease (VHL), an inherited disorder that predisposes individuals to pheochromocytomas and other tumors. Previous studies showed that when cells lack VHL, HIF1α is not degraded, resulting in a signal that resembles hypoxia. The authors found that loss of two genes that cause two distinct pheochromocytoma syndromes (the genes SDHB and SDHD, which encode the subunits B and D of succinate dehydrogenase, a component enzyme of the energy and respiratory system in mitochondria) also triggers a HIF1α response. The researchers further discovered that high H1F1α levels can suppress SDHB. This suggests a regulatory loop that further enhances the “hypoxia” profile of tumors. This finding provides a rational explanation for the shared features of these distinct syndromes and may be relevant for other cancers with a prominent hypoxic pattern.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.