Cavβ subunits in pancreatic β-cells

• Applicant: Privatdozent Dr. Anouar Belkacemi
• Subject Area: Pharmacology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569395765

Voltage-dependent Ca2+ channels (Cav) consist of a pore-forming α1 subunit and the accessory sub-units β, α2 and δ, for which Cav-independent functions have also been sporadically described. There are four Cavβ-subunits that are associated with a total of seven α1-subunits. In most cell types, there is no clear assignment of a particular Cavβ to one of the seven α1-subunits. The few exceptions are the Cav1.1 and Cavβ1a in skeletal muscle, the Cav1.3 and Cavβ2 in inner hair cells, the Cav1.4 and Cavβ2 in retinal photoreceptors, and the Cav1.2 and Cavβ2 in cardiac myocytes. Based on our preliminary work, pancreatic β-cells are an ideal system to further investigate the selectivity of Cavβ3 and Cavβ2 for different effector molecules mechanistically in the same cell. Our experiments show that selective knockout of Cavβ3 in β-cells does not affect Cav currents in these cells, whereas glu-cose-induced Ca2+ oscillations are enhanced, leading to increased insulin release, as well as more effective glucose clearance in vivo. In contrast, β-cell-specific deletion of Cavβ2 leads to a reduction of Cav currents as well as glucose clearance in vivo. The aim of this project is to elucidate the opposing functions of Cavβ2 and Cavβ3 with respect to Ca2+ signalling and their relevance for transcriptional activation and for glucose homeostasis. We will (i) investigate Ca2+ signalling and Cav currents in β-cells in intact islets and specifically in isolated β-cells and analyse whether Cavβ subunits affect transport/exocytosis of insulin granules. (ii) Identify the Cavβ3- (vs Cavβ2) specific molecular environment that underlies its selectivity for Cav channels and the IP3 receptor, in INS-1 β-cells. (iii) Elucidate the mechanisms by which Cavβ3 regulates insulin transcription, translation and secretion in-volving CaMKIV/CREB and MAFA. (iv) Investigate the role of Cavβ3 (vs Cavβ2) in the regulation of β-cell survival in type-2 diabetes disease mouse model. In addition to elucidating the functions specific to the two Cavβ subunits, the research project will provide new insights into the role of Ca2+ signalling in the pathophysiology of diabetes mellitus and thus provide the basis for future potential therapeutic strategies by manipulating Cavβ-dependent signalling pathways.

• DFG Programme: Research Grants