Biology subjects

Idevall-Hagren, O.

Publications and source records attributed to Idevall-Hagren, O..

8 recordsLinked to original sources

bioRxiv2026

Mitochondria-insulin granule crosstalk controls the early stages of granule maturation

Insulin secretion from pancreatic {beta}-cells is a tightly controlled process where hormone synthesis, granule formation and release are regulated in order to maintain whole body glucose homeostasis. Failure to produce or release insulin results in hyperglycemia that may develop into diabetes. Insulin-containing granules exist in different pools that have different propensity for release, yet what determined the fate of a granule after initial formation is not clear. In this study we aimed to identify key steps in the early life of an insulin granule that directs it towards release. Using two different methods for time-dependent labeling, we found that insulin granules shortly after budding from the trans-Golgi network associate with mitochondria. This organelle interaction involves the voltage-dependent anion channel (VDAC) and the vesicular nucleotide transporter (VNUT). Reduced VNUT expression prevented the recruitment of VDAC to insulin granules and redirected granules towards autophagy-dependent lysosomal degradation, resulting in reduced insulin content and impaired insulin secretion. These results show the requirement of granule-mitochondria crosstalk for normal progression through the early stages of the secretory pathway.

cell biology↗

bioRxiv2025

GABA-induced Ca2+ signaling in the primary cilium of neurons

The complex signaling processing in neurons requires establishment of autonomous compartments. The compartment that is unique for neurons and crucial for neuron-neuron signaling is the synapse. Another compartment, that neurons share with all other cells in the body, is the primary cilium. The primary cilium is a solitary organelle, present in almost every neuronal cell type, that extends into the extracellular space for detection of signals. Several GPCRs have been identified as ciliary receptors, and here we show that the metabotropic GABA receptor subtype 1 localizes to primary cilia of neurons across different regions of the mouse brain and that activation of these receptors initiates Ca2+ signaling that is restricted to this organelle. The excitatory nature of GABAergic signaling in primary cilia is opposite to GABA action in other neuronal domains, indicating distinct modes of action of this universal inhibitory neurotransmitter even within the same neuron.

neuroscience↗

bioRxiv2024

Follicle stimulating hormone receptor expression in human pancreas and effects on insulin secretion: A translational study

Follicle-stimulating hormone (FSH) is traditionally known for its role in reproduction, but recent studies suggest it may also influence metabolic processes. This study aimed to examine FSH receptor (FSHR) expression in human pancreatic islets and the direct effects of FSH on insulin secretion, as well as explore FSHs metabolic role during puberty, focusing on enhanced insulin secretion during this critical period. FSHR gene and protein expression were detected in isolated human pancreatic islets and co-localized with insulin-producing beta-cells. Additionally, FSH at prepubertal (0.1 IU/L) and pubertal concentrations (10 IU/L) significantly enhanced glucose-stimulated insulin secretion (GSIS) and increased intracellular cAMP concentrations in intact human pancreatic islets. In children with obesity from the Beta-JUDO cohort (n=608), plasma FSH levels were positively associated with several insulin secretion indices, particularly in pubertal children. These findings suggest that FSH has significant metabolic roles beyond reproduction, involving insulin secretion and potentially contributing to puberty-related hyperinsulinemia and insulin resistance.

cell biology↗

bioRxiv2024

Locally released somatostatin triggers cAMP and Ca2+ signaling in primary cilia to modulate pancreatic β-cell function

Somatostatin is produced and released from {delta}-cells within pancreatic islets of Langerhans and constitutes one of the most important negative regulators of islet hormone secretion. Somatostatin receptors (SSTR) are abundantly expressed in the islet cells and coupled to Gi and lowering of intracellular cAMP. We find that both SSTR3 and SSTR5 localize to primary cilia of {beta}-cells, and that activation of these receptors lowers the ciliary cAMP concentration. cAMP produced in the cytosol can enter the cilium through diffusion, but activation of ciliary SSTR3 specifically counteracts the rise of cAMP in the cilium. Moreover, we find that islet {delta}-cells are positioned near primary cilia of the other islet cell types and that somatostatin secretion is directed towards primary cilia. While acute exposure to somatostatin caused a rapid lowering of ciliary cAMP, sustained exposure promoted nuclear entry of the cilia-dependent transcription factor GLI2 through a mechanism that operated in parallel with the canonical Hedgehog pathway and depended on ciliary Ca2+ signaling. We also find that primary cilia length is reduced in islets from human donors with type-2 diabetes, which is associated with a reduction in cilia-{delta}-cell interactions. Our findings show that islet cell primary cilia constitute an important target of somatostatin action that endows it with the ability to regulate islet cell function beyond the acute suppression of hormone release.

cell biology↗

bioRxiv2023

OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion

Insulin secretion is the process whereby insulin-containing granules fuse with the plasma membrane of pancreatic {beta}-cells. Exocytosis is preceded by cargo loading and granule biogenesis at the Golgi, followed by maturation and transport of the secretory granules; processes that require modification of both the protein and lipid composition of the granules. Here, we show that insulin-containing secretory granules form physical contacts with the endoplasmic reticulum. The lipid exchange protein OSBP dynamically redistributes to ER-SG contacts in a process regulated by Ca2+ and cytosolic pH, and contributes to cholesterol loading of the granules. This process depends on granular PI(4)P and ER-localized VAPs, and is positively regulated by granular PI4-kinases and negatively regulated by granule-localized Sac2. Loss of Sac2 results in excess accumulation of cholesterol on insulin granules that is normalized when OSBP expression is reduced, and both acute inhibition and siRNA-mediated knockdown of OSBP suppresses glucose-stimulated insulin secretion without affecting insulin production or intracellular Ca2+ signaling. In conclusion, we show that lipid exchange at ER-granule contact sites is involved in the exocytic process, and propose that these contacts act as reaction centers with multimodal functions during insulin granule maturation.

cell biology↗

bioRxiv2021

The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signalling

The primary cilium is an organelle present in most adult mammalian cells and is thought of as an antenna for detection of a variety of signals. Here we use intact mouse pancreatic islets of Langerhans to investigate signalling properties of the primary cilium in {beta}-cells. Using cilia-targeted Ca2+ indicators we find that the resting Ca2+ concentration in the cilium is lower than that of the cytosol, and we uncover a Ca2+ extrusion mechanism in the cilium that effectively insulates the cilium from changes in cytosolic Ca2+. Stimuli that give rise to pronounced cytosolic Ca2+ concentration increases, such as glucose- and depolarization-induced Ca2+ influx, and mobilization of Ca2+ from the ER, was accompanied by minor increases in cilia Ca2+ concentrations that were spatially restricted to a small compartment at the base. Conversely, we observe pronounced Ca2+ concentration changes in the primary cilia of islet {beta}-cells that do not propagate into the cytosol and show that paracrine GABA signalling via cilia-localized GABA-B1-receptors is responsible for this Ca2+ signalling. Finally, we demonstrate that the cilia response to GABA involves ligand-dependent transport of GABA-B1 receptors into the cilium.

cell biology↗

bioRxiv2021

The endoplasmic reticulum-plasma membrane tethering protein TMEM24 is a regulator of cellular Ca2+ homeostasis

Endoplasmic reticulum (ER) - plasma membrane (PM) contacts are sites of lipid exchange and Ca2+ transport, and both lipid transport proteins and Ca2+ channels specifically accumulate at these locations. In pancreatic {beta}-cells, both lipid- and Ca2+ signaling are essential for insulin secretion. The recently characterized lipid transfer protein TMEM24 dynamically localize to ER-PM contact sites and provide phosphatidylinositol, a precursor of PI(4)P and PI(4,5)P2, to the plasma membrane. {beta}-cells lacking TMEM24 exhibit markedly suppressed glucose-induced Ca2+ oscillations and insulin secretion but the underlying mechanism is not known. We now show that TMEM24 only weakly interact with the PM, and dissociates in response to both diacylglycerol and nanomolar elevations of cytosolic Ca2+. Release of TMEM24 into the bulk ER membrane also enables direct interactions with mitochondria, and we report that loss of TMEM24 results in excessive accumulation of Ca2+ in both the ER and mitochondria and in impaired mitochondria function.

cell biology↗

bioRxiv2020

Piezo1 activation attenuates thrombin-induced blebbing in breast cancer cells

Cancer cells exploit a variety of migration modes to leave primary tumors and establish metastases, including amoeboid cell migration facilitated by bleb formation. Here we demonstrate that thrombin induces dynamic blebbing in the MDA-MB-231 breast cancer cell line, and confirm that PAR2 activation is sufficient to induce this effect. Cell confinement has been implicated as a driving force in bleb-based migration. Unexpectedly, we find that gentle contact compression, exerted using a "Cell Press" to mechanically stimulate cells, attenuated thrombin-induced blebbing with an associated increase in cytosolic calcium. Thrombin-induced blebbing was similarly attenuated using Yoda1, an agonist of the mechanosensitive calcium channel Piezo1, and its capacity to attenuate blebbing was impaired in Piezo1 depleted cells. Additionally, Piezo1 activation suppressed and reversed the thrombin-induced phosphorylation of ERM proteins, which are implicated in the blebbing process, and this activity was in part mediated through activation of the PP1A/PP2A family of serine/threonine phosphatases. Our results provide mechanistic insights into Piezo1 activation as a suppressor of dynamic blebbing, specifically that which is induced by thrombin.

cell biology↗