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Diabetes Autoantibodies Mediate Neural- and Endothelial Cell- Inhibitory Effects
Via 5-Hydroxytryptamine- 2 Receptor Coupled to Phospholipase C/Inositol
Triphosphate/Ca2+ Pathway
#MMPMID29805993
Zimering MB
J Endocrinol Diabetes
2017[]; 4
(4
): ? PMID29805993
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AIMS: To identify the G-protein coupled receptor(s) on neuroblastoma and
endothelial cells which mediate neural- and endothelial cell-inhibitory effects
in plasma autoantibodies from a subset of older type 2 diabetes with neurologic
and vascular co-morbidity. To determine the mechanism(s) of neurite retraction
induced by diabetic pathologies' auto antibodies. METHODS: Protein-A eluates from
plasma of 11 diabetic patients having nephropathy, moderate-severe obesity and/or
complications in which increased inflammation plays a role (depression,
Parkinson's disease, atrial fibrillation, obstructive sleep apnea) were tested
for neurite retraction and decreased survival in N2A neuroblastoma cells, and
decreased survival in pulmonary artery endothelial cells. Specific antagonists of
G protein coupled receptors belonging to the G alpha q subfamily of hetero
trimetric G proteins or the phospholipase C/inositol triphosphate/Ca2+ pathway
were tested for modulatory effects on diabetic pathologies' autoantibody-induced
N2A neurite retraction, or cell survival. RESULTS: Co-incubation with specific
antagonists of the 5-hydroxytryptamine- 2A receptor significantly prevented acute
N2A neurite retraction induced by 50-100 nM concentrations of diabetic
pathologies' autoantibodies. Protection against neurite retraction (M100907>
spiperone> ketanserin) closely paralleled the antagonists' potency order at the
5-HT2-AR. Neuroblastoma or endothelial cell death (after 24 hours incubation)
with 50-100 nM autoantibodies was completely or nearly completely (91%) prevented
by co-incubation with 200 nM M100907, a highly selective 5-HT2-AR antagonist.
Alpha-1 adrenergic, angiotensin II, metabotropic glutamate 5, or endothelin A
(100 nM-10然) receptor antagonists did not substantially inhibit
autoantibody-induced cell death. The intracellular calcium chelator (BAPTA-AM, 50
然) and inhibitors of the inositol triphosphate (IP3) receptor (2-APB, 50然), and
phospholipase C-gamma (U73144, 1然) each significantly protected against
autoantibody-induced acute N2A neurite retraction. CONCLUSION: These data suggest
that neural- and endothelial- inhibitory effects in autoantibodies from older
adult diabetes with nephropathy and obesity/inflammation-associated complications
are mediated by agonist autoantibodies directed against the 5-hydroxytryptamine 2
receptor positively coupled to the phospholipase C/inositol triphosphate/
cytosolic Ca2+ release pathway.
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