Calcium signaling is a universal carbon source signal transducer and effects an ionic memory of past carbon sources

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Summary Glucose is the preferred carbon source for most cells. However, cells may encounter other sources that can be utilized. How match their metabolic gene expression to source, beyond a general glucose repressive system (catabolite repression), remains little understood. By studying effect of up seven different on Snf1 phosphorylation and downstream regulated genes, we searched mechanism identifies sources. We found glycolysis metabolites glucose-6-phosphate (G6P) glucose-1-phosphate (G1P) play central role in adaptation The ratio G1P G6P activates an analogue calcium signaling via proton-exporter Pma1, regulate genes. pathway bifurcates with calcineurin reducing ADH2 (alcohol dehydrogenase) Cmk1 increasing ZWF1 (glucose-6-phosphate expression. Furthermore, not only by present source; it also past were able manipulate this ionic memory obtain high media containing galactose. Our findings provide universal which respond all

Language: Английский

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Calcium Signaling Is a Universal Carbon Source Signal Transducer and Effects an Ionic Memory of Past Carbon Sources

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2198 - 2198

Published: Feb. 28, 2025

Glucose is the preferred carbon source for most cells. However, cells may encounter other sources that can be utilized. How match their metabolic gene expression to source, beyond a general glucose repressive system (catabolite repression), remains little understood. By studying effect of up seven different on Snf1 phosphorylation and downstream regulated genes, we searched mechanism identifies sources. We found glycolysis metabolites glucose-6-phosphate (G6P) glucose-1-phosphate (G1P) play central role in adaptation The ratio G1P G6P activates analogue calcium signaling via proton-exporter Pma1 regulate genes. pathway bifurcates with calcineurin-reducing ADH2 (alcohol dehydrogenase) Cmk1-increasing ZWF1 (glucose-6-phosphate expression. Furthermore, not only by present source; it also past were able manipulate this ionic memory obtain high media containing galactose. Our findings provide universal which respond all

Language: Английский

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ER calcium stores contribute to glucose-induced Ca2+ waves and intercellular connectivity in mouse pancreatic islets

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

Abstract Defective insulin secretion is a hallmark of diabetes mellitus. Glucose-induced Ca 2+ oscillations are critical for the stimulation secretion, though mechanisms through which these propagate across islet poorly understood. Here, we use beta cell-targeted GCaMP6f to explore role endoplasmic reticulum (ER) mobilization in response submaximal (11mM) and hyperglycemic (25mM) glucose concentrations. Inhibition inositol 1,4,5 trisphosphate (IP 3 ) receptors, other ion channels, with 2-aminoethoxydiphenyl borate (2-APB) had minimal effects on initial peak or intercellular connectivity provoked by 11mM glucose. However, 2-APB lowered subsequent glucose-induced cytosolic increases at both 11 25mM Unexpectedly, activation IP receptors muscarinic acetylcholine receptor agonist carbachol impact elicited mM glucose, but waves 25 were more coordinated. To determine whether ER calcium was sufficient initiate next blocked sarco(endo)plasmic ATPase (SERCA) pumps thapsigargin, whilst preventing plasma membrane depolarization K ATP -channel opener, diazoxide. Under conditions, an increase followed secondary that slowly subsided. The application alongside diazoxide still enhanced dynamics, this activity uncoordinated cells connected. Our results show plays relatively minor initiation propagation On hand, stores required transition sustained waves. Highlights IP3R inhibition perturbs islets store insufficient generate cell GRAPHICAL ABSTRACT

Language: Английский

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Exploration of individual beta cell function over time in vivo: effects of hyperglycemia and glucagon-like peptide-1 receptor (GLP1R) agonism

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

The coordinated function of beta cells within the pancreatic islet is required for normal regulation insulin secretion and partly controlled by specialized "leader" highly connected "hub" beta-cell subpopulations. Whether these subpopulations are functionally stable in vivo remains unclear. Here, we establish an approach to monitor Ca 2+ dynamics individual over time, after engraftment into anterior eye chamber, where continuous blood perfusion near innervation pertain. Under normoglycemic conditions, network dynamics, behavior leaders hubs, remain at least seven days. Hyperglycemia, resulting from high-fat diet feeding or loss a host Gck allele, caused engrafted islets display incomplete abortive waves overall connectivity was diminished. Whereas hub cell numbers were lowered profoundly both disease models, largely persisted. Treatment with GLP1R agonist Exendin-4 led recovery islet-wide re-emergence minutes, effects incretin mimetic being more marked than those observed analogous treatments vitro . Similar observations made using 3-dimensional imaging across whole islet. Our findings thus suggest that incretins may act directly indirectly on vivo. described provide broad applicability exploration time living animal.

Language: Английский

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Sex-dependent additive effects of dorzagliatin and incretin on insulin secretion in a novel mouse model ofGCK-MODY

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 11, 2024

Abstract Glucokinase (GK) catalyses the key regulatory step in glucose-stimulated insulin secretion. Correspondingly, hetero– and homozygous mutations human GCK cause maturity-onset diabetes of young (GCK-MODY) permanent neonatal (PNDM), respectively. To explore possible utility glucokinase activators (GKA) glucagon–like receptor-1 (GLP-1) agonists these diseases, we have developed a novel hypomorphic Gck allele mice encoding an aberrantly spliced mRNA deleted for exons 2 3. In islets from knock-in (Gck KI/KI ) mice, GK immunoreactivity was reduced by >85%, secretion eliminated. Homozygous were smaller than wildtype littermates displayed frank (fasting blood glucose >18 mmol/L; HbA1c ∼12%), ketosis nephropathy. Heterozygous KI/+ intolerant (HbA1c ∼5.5%). Abnormal Ca 2+ dynamics beta cell-beta cell connectivity completely reversed recently-developed GKA, dorzagliatin, which largely inactive mouse islets. The GLP-1 receptor agonist exendin-4 improved tolerance male action potentiated but not female mice. Sex-dependent additive effects agents also observed on vitro . Combined treatment with GKA incretin may thus be useful -MODY or -PNDM. Article Highlights a. deficiency can drive (GCK-MODY; heterozygotes (GCK-PNDM; homozygotes b. We describe where aberrant splicing lowers activity to ∼85%. use activator, c. Whereas heterozygous mutant are mildly hyperglycemic, survive adulthood. Dorzagliatin potentiates activation sex-dependently d. drugs some forms

Language: Английский

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