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CaV1.3 Ca2+ channel in pancreatic ß-cell function and mass

CaV1.3 Ca2+ channel in pancreatic ß-cell function and mass

Petronel Tuluc (ORCID: 0000-0003-3660-6138)
  • Grant DOI 10.55776/P36053
  • Funding program Principal Investigator Projects
  • Status ongoing
  • Start October 1, 2022
  • End September 30, 2026
  • Funding amount € 408,604
  • E-mail

Disciplines

Biology (100%)

Keywords

    Cav1.3, Beta Cell, Insulin Release, T2Dm, ET-coupling, Calcium Channel

Abstract

Type 2 diabetes mellitus (T2DM) is caused by insufficient insulin secretion from pancreatic ß-cells or reduced insulin effects in the peripheral tissues. Glucose metabolism in pancreatic ß-cell leads to membrane depolarisation that activates the High Voltage-gated Calcium Channels (HVCCs). HVCC calcium influx increases electrical activity and intracellular calcium concentration triggering insulin release. Additionally, HVCCs are critical for the regulation of gene transcription that controls ß-cell differentiation and survival. ß-cells express several HVCC isoforms with CACNA1D gene encoding for CaV1.3-a1D being highly expressed in pancreatic islets of both mice and men. In humans CACNA1D polymorphisms resulting in channel loss-of-function (LOF) associate with increased susceptibility for Type 2 diabetes (T2DM) while CaV1.3 gain-of-function (GOF) mutations cause hyperinsulinemia and hypoglycaemia. Our unpublished data shows that CaV1.3 deletion in mice led to a 6-fold increase in DNA damage, a 3-fold decrease in proliferation markers, and ~20% reduced ß-cell mass. Functionally, CaV1.3 deletion caused a ~25% reduction in ß-cell calcium influx that resulted in delayed glucose- induced electrical activity with lower action potential frequency. However, the magnitude of the observed changes in calcium influx and electrical activity cannot explain how and why CaV1.3 deletion alters ß-cell mass. Therefore, we hypothesize that in pancreatic ß-cells CaV1.3 channel is coupled to gene transcription regulation. Using four different mouse models and state of the art methods including immunocytochemistry, electrophysiology, single cell RNAseq, and mass spectrometry we will test if either CaV1.3 calcium influx or channel complex is required for activity-dependent gene transcription, whether increasing Ca V1.3 activity alters ß-cell mass and function, and with which proteins CaV1.3 interacts. Identifying how Ca V1.3 LOF and GOF alter gene expression as well as identifying the Ca V1.3-interactome might give us critical clues on how to maintain ß-cell mass in T2DM. The in-depth characterization of the role of Ca V1.3 GOF on ß-cell function and mass will be crucial for understanding the disease aetiology in patients carrying GOF mutations. Additionally, our results will create testable hypotheses for neuroscience where Ca V1.3 GOF has been associated with neurodevelopmental and neurodegenerative disease.

Research institution(s)
  • Universität Innsbruck - 100%

Research Output

  • 13 Citations
  • 5 Publications
Publications
  • 2024
    Title Molecular mechanism responsible for sex differences in electrical activity of mouse pancreatic ß-cells
    DOI 10.1172/jci.insight.171609
    Type Journal Article
    Author Jacobo-Piqueras N
    Journal JCI Insight
    Link Publication
  • 2024
    Title A genetically encoded actuator boosts L-type calcium channel function in diverse physiological settings
    DOI 10.1126/sciadv.adq3374
    Type Journal Article
    Author Del Rivero Morfin P
    Journal Science Advances
    Link Publication
  • 2024
    Title A biallelic mutation in CACNA2D2 associated with developmental and epileptic encephalopathy affects calcium channel-dependent as well as synaptic functions of a2d-2
    DOI 10.1111/jnc.16197
    Type Journal Article
    Author Haddad S
    Journal Journal of Neurochemistry
    Link Publication
  • 2024
    Title Deletion of the a2d-1 calcium channel subunit increases excitability of mouse chromaffin cells
    DOI 10.1113/jp285681
    Type Journal Article
    Author Geisler S
    Journal The Journal of Physiology
    Pages 3793-3814
    Link Publication
  • 2023
    Title Excitation-secretion coupling in chromaffin cells of the adrenal gland: Where does calcium come from?
    DOI 10.1007/s00424-023-02867-z
    Type Journal Article
    Author Tuluc P
    Journal Pflügers Archiv - European Journal of Physiology
    Pages 3-4
    Link Publication

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