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Publication
Osteopontin activates the diabetes-associated potassium channel TALK-1 in
pancreatic ß-cells.
Authors Dickerson MT, Vierra NC, Milian SC, Dadi PK, Jacobson DA
Submitted By Submitted Externally on 5/10/2017
Status Published
Journal PLoS ONE
Year 2017
Date Published
Volume : Pages 12 : e0175069
PubMed Reference 28403169
Abstract Glucose-stimulated insulin secretion (GSIS) relies on ß-cell Ca2+ influx, which
is modulated by the two-pore-domain K+ (K2P) channel, TALK-1. A gain-of-function
polymorphism in KCNK16, the gene encoding TALK-1, increases risk for developing
type-2 diabetes. While TALK-1 serves an important role in modulating GSIS, the
regulatory mechanism(s) that control ß-cell TALK-1 channels are unknown.
Therefore, we employed a membrane-specific yeast two-hybrid (MYTH) assay to
identify TALK-1-interacting proteins in human islets, which will assist in
determining signaling modalities that modulate TALK-1 function. Twenty-one
proteins from a human islet cDNA library interacted with TALK-1. Some of these
interactions increased TALK-1 activity, including intracellular osteopontin
(iOPN). Intracellular OPN is highly expressed in ß-cells and is upregulated
under pre-diabetic conditions to help maintain normal ß-cell function; however,
the functional role of iOPN in ß-cells is poorly understood. We found that iOPN
colocalized with TALK-1 in pancreatic sections and coimmunoprecipitated with
human islet TALK-1 channels. As human ß-cells express two K+ channel-forming
variants of TALK-1, regulation of these TALK-1 variants by iOPN was assessed. At
physiological voltages iOPN activated TALK-1 transcript variant 3 channels but
not TALK-1 transcript variant 2 channels. Activation of TALK-1 channels by iOPN
also hyperpolarized resting membrane potential (Vm) in HEK293 cells and in
primary mouse ß-cells. Intracellular OPN was also knocked down in ß-cells to
test its effect on ß-cell TALK-1 channel activity. Reducing ß-cell iOPN
significantly decreased TALK-1 K+ currents and increased glucose-stimulated Ca2+
influx. Importantly, iOPN did not affect the function of other K2P channels or
alter Ca2+ influx into TALK-1 deficient ß-cells. These results reveal the first
protein interactions with the TALK-1 channel and found that an interaction with
iOPN increased ß-cell TALK-1 K+ currents. The TALK-1/iOPN complex caused Vm
hyperpolarization and reduced ß-cell glucose-stimulated Ca2+ influx, which is
predicted to inhibit GSIS.




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