Regulated resurfacing of a somatostatin receptor storage compartment fine-tunes pituitary secretion

Alshafie, Walaa; Francis, Vincent; Bednarz, Klaudia; Pan, Yingzhou Edward; Stroh, Thomas; McPherson, Peter S.

doi:10.1083/jcb.201904054

Cited by 13 publications

(13 citation statements)

References 87 publications

(107 reference statements)

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“…4f). Insensitivity to somatostatin is therefore the result of excessive receptor internalization, as has recently been shown for pituitary cells 49 .…”

Section: Resultsmentioning

confidence: 82%

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

et al. 2020

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Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cells of T2D donors, without changes in voltagedependent ion currents or granule trafficking. Dispersed α-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits α-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect α-cell insensitivity to paracrine inhibition at hyperglycemia.

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“…4f). Insensitivity to somatostatin is therefore the result of excessive receptor internalization, as has recently been shown for pituitary cells 49 .…”

Section: Resultsmentioning

confidence: 82%

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

et al. 2020

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“…The LRRK2 knock-out mice have been previously described by Hinkle and colleagues (2012). Rab10 knock-out AtT30 cells were a kind gift from Dr. Peter McPherson, and have been previously described (Alshafie et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

“…We used the following primary antibodies: GFP (Abcam ab1218); VPS35 (Abnova H00055737); VPS26 (a kind gift from J. Bonifacino, NICHD); FAM21C (Millipore ABT79); NEEP21/NSG1 (Genscript A01442); Rab11 (Abcam ab95375); MAP2 (Abcam ab5392); GluA1 (Millipore 05-763 855R); PSD95 (Thermo Scientific MA1-045); VGluT1 (Millipore AB5905); GluA1 extracellular (Millipore ABN241); Rab10 (Abcam 237703); and GluA1 (Alomone AGP-009). Rab10 specificity was tested using Rab10 knock-out AtT30 cells (a kind gift from Dr. Peter McPherson; described in (Alshafie et al, 2020)) and cultured cortical neurons (Fig. 8 Supp.…”

Section: Immunocytochemistry and Imaging Analysismentioning

confidence: 99%

“…7 B.v; Kruskal-Wallis p<0.02; WT-Het *p<0.02; Het-Ho *p<0.02), suggesting a genotype-dependent effect of LRRK2 kinase inhibition on AMPAR surface expression, or an interaction with the apparent effect of the vehicle Captisol. Rab10 is involved in actin dynamics at recycling endosomes (P. and transport of retromer cargoes including GLR-1 (Alshafie et al, 2020;Bruno, Brumfield, Chaudhary, Iaea, & McGraw, 2016;Y. Chen et al, 2005;Glodowski, Chen, Schaefer, Grant, & Rongo, 2007;Pan, Zaarur, Singh, Morin, & Kandror, 2017).…”

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confidence: 99%

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Surface GluA1 and glutamatergic transmission are increased in cortical neurons of a VPS35 D620N knock-in mouse model of parkinsonism and altered by LRRK2 kinase inhibition

Kadgien

Kamesh

Khinda

et al. 2021

Preprint

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Vacuolar protein sorting 35 (VPS35) regulates receptor recycling from endosomes. A missense mutation in VPS35 (D620N) leads to autosomal-dominant, late-onset Parkinson’s disease. Here, we use a VPS35 D620N knock-in mouse to study the neurobiology of this mutation. In brain tissue, we confirm previous findings that the mutation results in reduced binding of VPS35 with WASH-complex member FAM21, and robustly elevated phosphorylation of the LRRK2 kinase substrate Rab10. In cultured cortical neurons, the mutation results in increased endosomal recycling protein density (VPS35-FAM21 co-clusters and Rab11 clusters), glutamate release, and GluA1 surface expression. LRRK2 kinase inhibition exerted genotype-specific effects on GluA1 surface expression, but did not impact glutamate release phenotypes. These results improve our understanding of the early effects of the D620N mutation on cellular functions that are specific to neurons. These observations provide candidate pathophysiological pathways that may drive eventual transition to late-stage parkinsonism in VPS35 families, and support a synaptopathy model of neurodegeneration.

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“…SSTR5 modifies HPA axis stress response and attenuates corticotroph responses to corticotropin releasing factor (CRF) by post-transcriptionally suppressing CRFR1 expression and function via miR-449 ( 27 ). In pituitary AtT20-cells, CRF (100nM) induced rapid Rab10-dependent resurfacing of endocytosed SSTR2 via CRFR1, providing a feedback mechanism to inhibit CRFR signaling ( 28 ). Hypoxia stimulated expression of SSTmRNA and protein in the periventricular nucleus of the hypothalamus and decreased GH release from pituitary and body weight gain in rat.…”

Section: Sst-endocrine Cells In Non-gastrointestinal Tractmentioning

confidence: 99%

Versatile Functions of Somatostatin and Somatostatin Receptors in the Gastrointestinal System

Shamsi¹,

Chatoo²,

Xu³

et al. 2021

Front. Endocrinol.

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Somatostatin (SST) and somatostatin receptors (SSTRs) play an important role in the brain and gastrointestinal (GI) system. SST is produced in various organs and cells, and the inhibitory function of somatostatin-containing cells is involved in a range of physiological functions and pathological modifications. The GI system is the largest endocrine organ for digestion and absorption, SST-endocrine cells and neurons in the GI system are a critical effecter to maintain homeostasis via SSTRs 1-5 and co-receptors, while SST-SSTRs are involved in chemo-sensory, mucus, and hormone secretion, motility, inflammation response, itch, and pain via the autocrine, paracrine, endocrine, and exoendocrine pathways. It is also a power inhibitor for tumor cell proliferation, severe inflammation, and post-operation complications, and is a first-line anti-cancer drug in clinical practice. This mini review focuses on the current function of producing SST endocrine cells and local neurons SST-SSTRs in the GI system, discusses new development prognostic markers, phosphate-specific antibodies, and molecular imaging emerging in diagnostics and therapy, and summarizes the mechanism of the SST family in basic research and clinical practice. Understanding of endocrines and neuroendocrines in SST-SSTRs in GI will provide an insight into advanced medicine in basic and clinical research.

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Regulated resurfacing of a somatostatin receptor storage compartment fine-tunes pituitary secretion

Cited by 13 publications

References 87 publications

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

Surface GluA1 and glutamatergic transmission are increased in cortical neurons of a VPS35 D620N knock-in mouse model of parkinsonism and altered by LRRK2 kinase inhibition

Versatile Functions of Somatostatin and Somatostatin Receptors in the Gastrointestinal System

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