Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A hierarchical hormonal cascade along the hypothalamic-pituitary-adrenal axis orchestrates bodily responses to stress. Although corticotropin-releasing hormone (CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagogin's Ca(2+) sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogin's loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness.
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PMID:A secretagogin locus of the mammalian hypothalamus controls stress hormone release. 2543 Jul 41

Secretagogin (SCGN), a multifunctional, Ca²⁺ binding, regulatory protein, known to regulate insulin release, has recently been implicated in the control of stress-related corticotropin-releasing hormone (CRH) secretion. Localization of SCGN to multiple intracellular (such as cytosol, nucleus, and endoplasmic reticulum) and extracellular sites appears to provide multifunctional capabilities; however, the structural elements conferring such a widespread cellular distribution to SCGN remain unidentified. We report that the spatial and functional attributes of SCGN plausibly originate from the interplay between Ca²⁺ and its redox state. The mutation of selective Cys residues provides further insights into the origin and mode of redox responsiveness. In the reducing milieu, SCGN exhibits a higher affinity for Ca²⁺, and more stability than in the oxidizing environment, suggesting it is a redox-responsive Ca²⁺ sensor protein, which is further supported by its response to dithiothreitol (reducing stress) in MIN6 cells. Our data provide a biophysical and biochemical explanation for the diverse localization of SCGN in the cellular scenario and beyond the cell.
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PMID:Secretagogin Is a Redox-Responsive Ca²⁺ Sensor. 2799 25

Hormonal responses to acute stress rely on the rapid induction of corticotropin-releasing hormone (CRH) production in the mammalian hypothalamus, with subsequent instructive steps culminating in corticosterone release at the periphery. Hypothalamic CRH neurons in the paraventricular nucleus of the hypothalamus are therefore considered as 'stress neurons'. However, significant morphological and functional diversity among neurons that can transiently produce CRH in other hypothalamic nuclei has been proposed, particularly as histochemical and molecular biology evidence associates CRH to both GABA and glutamate neurotransmission. Here, we review recent advances through single-cell RNA sequencing and circuit mapping to suggest that CRH production reflects a state switch in hypothalamic neurons and thus confers functional competence rather than being an identity mark of phenotypically segregated neurons. We show that CRH mRNA transcripts can therefore be seen in GABAergic, glutamatergic and dopaminergic neuronal contingents in the hypothalamus. We then distinguish 'stress neurons' of the paraventricular nucleus that constitutively express secretagogin, a Ca²⁺ sensor critical for the stimulus-driven assembly of the molecular machinery underpinning the fast regulated exocytosis of CRH at the median eminence. Cumulatively, we infer that CRH neurons are functionally and molecularly more diverse than previously thought.
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PMID:Molecular diversity of corticotropin-releasing hormone mRNA-containing neurons in the hypothalamus. 2805 67

Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin-releasing hormone-releasing neurons innervate ependymal cells of the 3^rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal-regulated kinase 1 and tyrosine hydroxylase with the Ca²⁺-sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress-induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate-limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long-lasting cortical excitability following acute stress.
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PMID:Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress. 3036 65

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