Dataset Information

Blocking Ca²⁺ Channel ?₃ Subunit Reverses Diabetes.

ABSTRACT: Voltage-gated Ca²⁺ channels (Ca_v) are essential for pancreatic beta cell function as they mediate Ca²⁺ influx, which leads to insulin exocytosis. The ?3 subunit of Ca_v (Ca_v?₃) has been suggested to regulate cytosolic Ca²⁺ ([Ca²⁺]_i) oscillation frequency and insulin secretion under physiological conditions, but its role in diabetes is unclear. Here, we report that islets from diabetic mice show Ca_v?₃ overexpression, altered [Ca²⁺]_i dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Ca_v?₃-deficient (Ca_v?₃^-/-) mice showed improved islet function and enhanced glucose tolerance. Normalization of Ca_v?₃ expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca²⁺]_i dynamics and impaired insulin secretion. Importantly, transplantation of Ca_v?₃^-/- islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Ca_v?₃ overexpression in human islets also impaired insulin secretion. We thus suggest that Ca_v?₃ may serve as a druggable target for diabetes treatment.

SUBMITTER: Lee K

PROVIDER: S-EPMC6083041 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Blocking Ca2+ Channel β3 Subunit Reverses Diabetes.

Lee Kayoung K Kim Jaeyoon J Köhler Martin M Yu Jia J Shi Yue Y Yang Shao-Nian SN Ryu Sung Ho SH Berggren Per-Olof PO

Cell reports 20180701 4

Voltage-gated Ca2+ channels (Cav) are essential for pancreatic beta cell function as they mediate Ca2+ influx, which leads to insulin exocytosis. The β3 subunit of Cav (Cavβ3) has been suggested to regulate cytosolic Ca2+ ([Ca2+]i) oscillation frequency and insulin secretion under physiological conditions, but its role in diabetes is unclear. Here, we report that islets from diabetic mice show Ca<s ...[more]

PMID: 30044988

Similar Datasets

Project description:Mammalian circadian (24 h) rhythms are timed by the pattern of spontaneous action potential firing in the suprachiasmatic nucleus (SCN). This oscillation in firing is produced through circadian regulation of several membrane currents, including large-conductance Ca2+- and voltage-activated K+ (BK) and L-type Ca2+ channel (LTCC) currents. During the day steady-state BK currents depend mostly on LTCCs for activation, whereas at night they depend predominantly on ryanodine receptors (RyRs). However, the contribution of these Ca2+ channels to BK channel activation during action potential firing has not been thoroughly investigated. In this study, we used a pharmacological approach to determine that both LTCCs and RyRs contribute to the baseline membrane potential of SCN action potential waveforms, as well as action potential-evoked BK current, during the day and night, respectively. Since the baseline membrane potential is a major determinant of circadian firing rate, we focused on the LTCCs contributing to low voltage activation of BK channels during the subthreshold phase. For these experiments, two LTCC subtypes found in SCN (CaV1.2 and CaV1.3) were coexpressed with BK channels in heterologous cells, where their differential contributions could be separately measured. CaV1.3 channels produced currents that were shifted to more hyperpolarized potentials compared with CaV1.2, resulting in increased subthreshold Ca2+ and BK currents during an action potential command. These results show that although multiple Ca2+ sources in SCN can contribute to the activation of BK current during an action potential, specific BK-CaV1.3 partnerships may optimize the subthreshold BK current activation that is critical for firing rate regulation.NEW & NOTEWORTHY BK K+ channels are important regulators of firing. Although Ca2+ channels are required for their activation in excitable cells, it is not well understood how BK channels activate using these Ca2+ sources during an action potential. This study demonstrates the differences in BK current activated by CaV1.2 and CaV1.3 channels in clock neurons and heterologous cells. The results define how specific ion channel partnerships can be engaged during distinct phases of the action potential.

Dataset Information

Blocking Ca²⁺ Channel ?₃ Subunit Reverses Diabetes.

Publications

Blocking Ca<sup>2+</sup> Channel β<sub>3</sub> Subunit Reverses Diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Blocking Ca2+ Channel ?3 Subunit Reverses Diabetes.

Publications

Blocking Ca<sup>2+</sup> Channel β<sub>3</sub> Subunit Reverses Diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Blocking Ca²⁺ Channel ?₃ Subunit Reverses Diabetes.