Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) play a central role in stimulation of feeding. They sense and integrate peripheral and central signals, including ghrelin and leptin. However, the mechanisms of interaction of these hormones in NPY neurons are largely unknown. This study explored the interaction and underlying signaling cross talk between ghrelin and leptin in NPY neurons. Cytosolic Ca(2+) concentration ([Ca(2+)](i)) in single neurons isolated from ARC of adult rats was measured by fura-2 microfluorometry. Ghrelin increased [Ca(2+)](i) in 31% of ARC neurons. The [Ca(2+)](i) increases were inhibited by blockers of phospholipase C, adenylate cyclase, and protein kinase A. Ghrelin-induced [Ca(2+)](i) increases were suppressed by subsequent administration of leptin. Fifteen of 18 ghrelin-activated, leptin-suppressed neurons (83%) contained NPY. Leptin suppression of ghrelin responses was prevented by pretreatment with inhibitors of phosphatidylinositol 3-kinase and phosphodiesterase 3 (PDE3) but not MAPK. ATP-sensitive potassium channel inhibitors and activators did not prevent and mimic leptin suppression, respectively. Although leptin phosphorylated signal-transducer and activator of transcription 3 (STAT3) in NPY neurons, neither STAT3 inhibitor nor genetic STAT3 deletion altered leptin suppression of ghrelin responses. Furthermore, orexigenic effect of intracerebroventricular ghrelin in rats was counteracted by leptin in a PDE3-dependent manner. These findings indicate that ghrelin increases [Ca(2+)](i) via mechanisms depending on phospholipase C and adenylate cyclase-PKA pathways in ARC NPY neurons and that leptin counteracts ghrelin responses via a phosphatidylinositol 3-kinase-PDE3 pathway. This interaction may play an important role in regulating ARC NPY neuron activity and, thereby, feeding.
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PMID:Leptin suppresses ghrelin-induced activation of neuropeptide Y neurons in the arcuate nucleus via phosphatidylinositol 3-kinase- and phosphodiesterase 3-mediated pathway. 1730 62

Neuropeptide Y (NPY), a member of the pancreatic polypeptide family, is an orexigenic hormone. GnRH-1 neurons express NPY receptors. This suggests a direct link between metabolic function and reproduction. However, the effect of NPY on GnRH-1 cells has been variable, dependent on metabolic and reproductive status of the animal. This study circumvents these issues by examining the role of NPY on GnRH-1 neuronal activity in an explant model that is based on the extra-central nervous system origin of GnRH-1 neurons. These prenatal GnRH-1 neurons express many receptors found in GnRH-1 neurons in the brain and use similar transduction pathways. In addition, these GnRH-1 cells exhibit spontaneous and ligand-induced oscillations in intracellular calcium as well as pulsatile calcium-controlled GnRH-1 release. Single-cell PCR determined that prenatal GnRH-1 neurons express the G protein-coupled Y1 receptor (Y1R). To address the influence of NPY on GnRH-1 neuronal activity, calcium imaging was used to monitor individual and population dynamics. NPY treatment, mimicked with Y1R agonist, significantly decreased the number of calcium peaks per minute in GnRH-1 neurons and was prevented by a Y1R antagonist. Pertussis toxin blocked the effect of NPY on GnRH-1 neuronal activity, indicating the coupling of Y1R to inhibitory G protein. The NPY-induced inhibition was independent of the adenylate cyclase pathway but mediated by the activation of G protein-coupled inwardly rectifying potassium channels. These results indicate that at an early developmental stage, GnRH-1 neuronal activity can be directly inhibited by NPY via its Y1R.
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PMID:Neuropeptide Y directly inhibits neuronal activity in a subpopulation of gonadotropin-releasing hormone-1 neurons via Y1 receptors. 2035 16


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