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题名:The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis.
作者:LIU B; HASSAN Z; AMISTEN S; KING AJ; BOWE JE; HUANG GC; JONES PM; PERSAUD SJ;
来源:Diabetologia. 2013 Nov;56(11):2467-76. doi: 10.1007/s00125-013-3022-x. Epub 2013 [ IF= 6.49 ] ]
URL :10.1007/s00125-013-3022-x
日期:20131203
摘要:AIMS/HYPOTHESIS: Chemokine (C-C motif) ligand 5 (CCL5) acts at C-C chemokine
receptors (CCRs) to promote immune cell recruitment to sites of inflammation, but
is also an agonist at G-protein-coupled receptor 75 (GPR75), which has very
limited homology with CCRs. GPR75 is coupled to Gq to elevate intracellular
calcium, so we investigated whether islets express this receptor and whether its
activation by CCL5 increases beta cell calcium levels and insulin secretion.
METHODS: Islet CCL5 receptor mRNA expression was measured by quantitative RT-PCR
and GPR75 was detected in islets by western blotting and immunohistochemistry. In
some experiments GPR75 was downregulated by transient transfection with small
interfering RNA. Real-time changes in intracellular calcium were determined by
single-cell microfluorimetry. Dynamic insulin secretion from perifused islets was
quantified by radioimmunoassay. Glucose homeostasis in lean and obese mice was
determined by measuring glucose and insulin tolerance, and insulin secretion in
vivo. RESULTS: Mouse and human islets express GPR75 and its ligand CCL5.
Exogenous CCL5 reversibly increased intracellular calcium in beta cells via
GPR75, this phenomenon being dependent on phospholipase C activation and calcium
influx. CCL5 also stimulated insulin secretion from mouse and human islets in
vitro, and improved glucose tolerance in lean mice and in a mouse model of
hyperglycaemia and insulin resistance (ob/ob). The improvement in glucose
tolerance was associated with enhanced insulin secretion in vivo, without changes
in insulin sensitivity. CONCLUSIONS/INTERPRETATION: Although CCL5 is implicated
in the pathogenesis of diabetes through activation of CCRs, it has beneficial
effects on beta cells through GPR75 activation.

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