TALK-1 channels control β cell endoplasmic reticulum Cahomeostasis.
AUTHORS
- PMID: 28928238 [PubMed].
- PMCID: PMC5672804.
- NIHMSID: NIHMS914299
ABSTRACT
Cahandling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic β cell function and becomes perturbed during the pathogenesis of diabetes. ER Cahomeostasis is determined by ion movements across the ER membrane, including Kflux through Kchannels. We demonstrated that Kflux through ER-localized TALK-1 channels facilitated Carelease from the ER in mouse and human β cells. We found that β cells from mice lacking TALK-1 exhibited reduced basal cytosolic Caand increased ER Caconcentrations, suggesting reduced ER Caleak. These changes in Cahomeostasis were presumably due to TALK-1-mediated ER Kflux, because we recorded Kcurrents mediated by functional TALK-1 channels on the nuclear membrane, which is continuous with the ER. Moreover, overexpression of K-impermeable TALK-1 channels in HEK293 cells did not reduce ER Castores. Reduced ER Cacontent in β cells is associated with ER stress and islet dysfunction in diabetes, and islets from TALK-1-deficient mice fed a high-fat diet showed reduced signs of ER stress, suggesting that TALK-1 activity exacerbated ER stress. Our data establish TALK-1 channels as key regulators of β cell ER Caand suggest that TALK-1 may be a therapeutic target to reduce ER Cahandling defects in β cells during the pathogenesis of diabetes.
Cahandling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic β cell function and becomes perturbed during the pathogenesis of diabetes. ER Cahomeostasis is determined by ion movements across the ER membrane, including Kflux through Kchannels. We demonstrated that Kflux through ER-localized TALK-1 channels facilitated Carelease from the ER in mouse and human β cells. We found that β cells from mice lacking TALK-1 exhibited reduced basal cytosolic Caand increased ER Caconcentrations, suggesting reduced ER Caleak. These changes in Cahomeostasis were presumably due to TALK-1-mediated ER Kflux, because we recorded Kcurrents mediated by functional TALK-1 channels on the nuclear membrane, which is continuous with the ER. Moreover, overexpression of K-impermeable TALK-1 channels in HEK293 cells did not reduce ER Castores. Reduced ER Cacontent in β cells is associated with ER stress and islet dysfunction in diabetes, and islets from TALK-1-deficient mice fed a high-fat diet showed reduced signs of ER stress, suggesting that TALK-1 activity exacerbated ER stress. Our data establish TALK-1 channels as key regulators of β cell ER Caand suggest that TALK-1 may be a therapeutic target to reduce ER Cahandling defects in β cells during the pathogenesis of diabetes.
Tags: 2017