http://www.ncbi.nlm.nih.gov/pubmed/17182843
Mol Biol Cell. 2007 Feb;18(2):688-96. Epub 2006 Dec 20.
Exophilin4/Slp2-a targets glucagon granules to the plasma membrane through unique Ca2+-inhibitory phospholipid-binding activity of the C2A domain.
Yu M1, Kasai K, Nagashima K, Torii S, Yokota-Hashimoto H, Okamoto K, Takeuchi T, Gomi H, Izumi T.Abstract
Rab27a
and Rab27b have recently been recognized to play versatile roles in
regulating the exocytosis of secretory granules and lysosome-related
organelles by using multiple effector proteins.
However, the precise roles of these effector proteins in particular cell types largely remain uncharacterized, except for those in pancreatic beta cells and in melanocytes.
Here, we showed that one of the Rab27a/b effectors, exophilin4/Slp2-a, is specifically expressed in pancreatic alpha cells, in contrast to another effector, granuphilin, in beta cells. Like granuphilin toward insulin granules, exophilin4 promotes the targeting of glucagon granules to the plasma membrane.
Although the interaction of granuphilin with syntaxin-1a is critical for the targeting activity, exophilin4 does this primarily through the affinity of its C2A domain toward the plasma membrane phospholipids phosphatidylserine and phosphatidylinositol-4,5-bisphosphate (PIP2) .
Notably, the binding activity to phosphatidylserine is inhibited by a physiological range of the Ca(2+) concentration attained after secretagogue stimulation, which presents a striking contrast to the Ca(2+)-stimulatory activity of the C2A domain of synaptotagmin I. Analyses of the mutant suggested that this novel Ca(2+)-inhibitory phospholipid-binding activity not only mediates docking but also modulates the subsequent fusion of the secretory granules.
However, the precise roles of these effector proteins in particular cell types largely remain uncharacterized, except for those in pancreatic beta cells and in melanocytes.
Here, we showed that one of the Rab27a/b effectors, exophilin4/Slp2-a, is specifically expressed in pancreatic alpha cells, in contrast to another effector, granuphilin, in beta cells. Like granuphilin toward insulin granules, exophilin4 promotes the targeting of glucagon granules to the plasma membrane.
Although the interaction of granuphilin with syntaxin-1a is critical for the targeting activity, exophilin4 does this primarily through the affinity of its C2A domain toward the plasma membrane phospholipids phosphatidylserine and phosphatidylinositol-4,5-bisphosphate (PIP2) .
Notably, the binding activity to phosphatidylserine is inhibited by a physiological range of the Ca(2+) concentration attained after secretagogue stimulation, which presents a striking contrast to the Ca(2+)-stimulatory activity of the C2A domain of synaptotagmin I. Analyses of the mutant suggested that this novel Ca(2+)-inhibitory phospholipid-binding activity not only mediates docking but also modulates the subsequent fusion of the secretory granules.
- PMID:
- 17182843
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC1783794
http://www.ncbi.nlm.nih.gov/pubmed/24507615
Biophys J. 2014 Feb 4;106(3):741-51. doi: 10.1016/j.bpj.2013.11.4504.
Malli haimasaarekkeen A-solun kaksoismekanismista, jolla glukoosi (sokeri) vaimentaa GLUKAGONIN eritystä
Malli haimasaarekkeen A-solun kaksoismekanismista, jolla glukoosi (sokeri) vaimentaa GLUKAGONIN eritystä
Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion. Watts M1, Sherman A2.Abstract
On kyllä ymmärretty hyvin, millä tavalla glukoosi ( sokeri) aiheuttaa Beta-soluissa INSULIININ erityksen.
Huolimatta vuosien tutkimuksista ei ole kuitenkaan pystytty selvittämään yhtä hyvin A_solujen GLUKAGONI-eritystä. On oletettu, että glukoosi (sokeri) säätelee GLUKAGONIN erityksen alentamalla johtuvuutta joko ulosjohtavassa ATP;sta riippuvassa kaliumkanavassa (Katp) tai sisävarastoon operoivassa virrassa (SOC) . On kehitetty matemaattinen malli ja tätä oletusta on testattu koe-eläimissä ja todettu että molemmat mekanismit ovat mahdollisia
Huolimatta vuosien tutkimuksista ei ole kuitenkaan pystytty selvittämään yhtä hyvin A_solujen GLUKAGONI-eritystä. On oletettu, että glukoosi (sokeri) säätelee GLUKAGONIN erityksen alentamalla johtuvuutta joko ulosjohtavassa ATP;sta riippuvassa kaliumkanavassa (Katp) tai sisävarastoon operoivassa virrassa (SOC) . On kehitetty matemaattinen malli ja tätä oletusta on testattu koe-eläimissä ja todettu että molemmat mekanismit ovat mahdollisia
- The mechanism by which glucose induces insulin secretion in β-cells is fairly well understood. Despite years of research, however, the mechanism of glucagon secretion in α-cells is still not well established. It has been proposed that glucose regulates glucagon secretion by decreasing the conductance of either outward ATP-dependent potassium channels (K(ATP) or an inward store-operated current (SOC). We have developed a mathematical model based on mouse data to test these hypotheses and found that both mechanisms are possible
- Glucose metabolism closes K(ATP) channels, which depolarizes the cell but paradoxically reduces calcium influx by inactivating voltage-dependent calcium and sodium channels and decreases secretion.
- Glucose metabolism also activates SERCA pumps, which fills the endoplasmic reticulum and hyperpolarizes the cells by reducing the inward current through SOC channels and again suppresses glucagon secretion. We find further that the two mechanisms can combine to account for the nonmonotonic dependence of secretion on glucose observed in some studies, an effect that cannot be obtained with either mechanism alone.
Kommenttini.
Vuodelta 2015 valaiseva artikkeli, jossa A-solun glukoosi-6-fosfaattisensori toiminta näkyy
http://www.medbio.info/Horn/Time%203-4/secretion_of_insulin_and_glucagon_nov_2007.htm
Huom. Jos insuliinista on vaje, tämäkään glukoosin metaboliitin tunnistamisprosessi G6P-muoto) ei ole normaalia. Siis A-solun normaalitoiminnalle onedellytys betasolun normaali toiminta. joten virhe betasolutoiminnasa pahentaa tilannetta progressiivisesti käsittääkseni. Tässä kyllä tulee mieleen se että paha exogeeninen tekijä on ravinnon sokerin liikamäärä eikä sen nykyiset lievät rajoitukset vastaa tilanteen ehdotonta vakavuutta. Voi vain kuvitella, missä tulehdustilasas kasvavan sukupolven haimasaarekkeet jatkuvasti ovat.
Diabetekseen johtavina tästä saareketasosta voi nähdä monta exogeenista tekijää. liika sokeri on yiksi, fytiinin osuuden aliarviointi tai tuntemattomuus on toinen, rikkiaineenvaihdunnan hahmottamisen vaje kolmas, energian ylitarjonta kaikissa energia-aineryhmissä neljässä, epäorgaanisen fosfaatin liikakuormitus, Luuston rikki-typpi-fosfaatti tasapainossakin on jotain, mikä johtaa kalsiumaineenvaihdunna kaaokseen.
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