Molecular Endocrinology Group (Head: P. Tuluc)
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- Stefanie Geisler |
Internal Collaborators:
- CavX PhD Program "Calcium channels in excitable cells" - CMBI
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AIM
In many excitable cells plasma membrane depolarization leads to the activation of High Voltage-gated Calcium Channels (HVCC). Depending on the cell type, the HVCC calcium influx triggers different effector functions like muscle contraction, synaptic transmission, or hormone release. Additionally, HVCC calcium influx is critical for gene transcription regulation, cell differentiation and survival. HVCCs are transmembrane protein complexes formed by the pore-forming α1 subunit and the auxiliary intracellular β, extracellular/transmembrane α2δ and, in certain cell types the transmembrane g subunits. Based on their unique biophysical properties and pharmacological profile the HVCC α1 subunits are classified in L-type (Cav1.1, Cav1.2, Cav1.3, Cav1.4), P/Q- (Cav2.1), N-(Cav2.2) and R-type (Cav2.3). While certain cell types like skeletal and cardiac muscle or retina express exclusively only one isoform, the endocrine cells like pancreatic β-cells or chromaffin cells of the adrenal medulla express at least 4 different isoforms each.
The Tuluc lab is interested in functional properties and physiological role of high voltage-gated calcium channels (HVCC) isoforms in endocrine cells where they play a key role in hormone synthesis and release.
Methods
The lab utilizes a combination of electrophysiological (voltage-clamp, current-clamp), molecular, biochemical and immunofluorescent methods. To understand the HVCC structure-function properties we express the channels in heterologous systems where the properties of the channel can be studied under defined and simplified conditions. The physiological role of the channel in hormone release is investigated in native micro organs (pancreatic islets) or isolated primary cells (pancreatic β-cells or adrenal medulla chromaffin cells) obtained from either wild-type mice or genetically modified mouse models.
Currently, our lab focuses on three research topics
- Role of CaV1.3 L-type calcium channel loss-of-function and gain-of-function in β-cell survival and function (Ryo, Steffi).
- Role of Stac2 adaptor protein in β-cell survival and function (Laura).
- Role of Stac2 adaptor protein in mouse chromaffin cell function (Steffi).
- Effect of gabapentin on insulin and cathecholamine secretion (Ryo).
Selected publications
Most relevant publications (1-12):
1. Jacobo-Piqueras, N., Theiner, T., Geisler, S. M. & Tuluc, P. Molecular mechanism responsible for sex differences in electrical activity of mouse pancreatic beta cells. JCI Insight 9, doi:10.1172/jci.insight.171609 (2024)
https://www.ncbi.nlm.nih.gov/pubmed/38358819
2. Ortner, N. J., Sah, A., Paradiso, E., Shin, J., Stojanovic, S., Hammer, N., Haritonova, M., Hofer, N. T., Marcantoni, A., Guarina, L., Tuluc, P., Theiner, T., Pitterl, F., Ebner, K., Oberacher, H., Carbone, E., Stefanova, N., Ferraguti, F., Singewald, N., Roeper, J. & Striessnig, J. The human channel gating-modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome-like phenotype in mice. JCI Insight 8, doi:10.1172/jci.insight.162100 (2023)
https://www.ncbi.nlm.nih.gov/pubmed/37698939
3. Fernandez-Quintero, M. L., El Ghaleb, Y., Tuluc, P., Campiglio, M., Liedl, K. R. & Flucher, B. E. Structural determinants of voltage-gating properties in calcium channels. elife 10, doi:10.7554/eLife.64087 (2021)
https://www.ncbi.nlm.nih.gov/pubmed/33783354
4. El Ghaleb, Y., Schneeberger, P. E., Fernandez-Quintero, M. L., Geisler, S. M., Pelizzari, S., Polstra, A. M., van Hagen, J. M., Denecke, J., Campiglio, M., Liedl, K. R., Stevens, C. A., Person, R. E., Rentas, S., Marsh, E. D., Conlin, L. K., Tuluc, P., Kutsche, K. & Flucher, B. E. CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders. Brain 144, 2092-2106, doi:10.1093/brain/awab101 (2021)
https://www.ncbi.nlm.nih.gov/pubmed/33704440
5. Hofer, N. T., Tuluc, P., Ortner, N. J., Nikonishyna, Y. V., Fernandes-Quintero, M. L., Liedl, K. R., Flucher, B. E., Cox, H. & Striessnig, J. Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder. Mol Autism 11, 4, doi:10.1186/s13229-019-0310-4 (2020)
https://www.ncbi.nlm.nih.gov/pubmed/31921405
6. Monteleone, S., Lieb, A., Pinggera, A., Negro, G., Fuchs, J. E., Hofer, F., Striessnig, J., Tuluc, P. & Liedl, K. R. Mechanisms Responsible for omega-Pore Currents in Ca(v) Calcium Channel Voltage-Sensing Domains. Biophys J 113, 1485-1495, doi:10.1016/j.bpj.2017.08.010 (2017)
https://www.ncbi.nlm.nih.gov/pubmed/28978442
7. Mastrolia, V., Flucher, S. M., Obermair, G. J., Drach, M., Hofer, H., Renstrom, E., Schwartz, A., Striessnig, J., Flucher, B. E. & Tuluc, P. Loss of alpha(2)delta-1 Calcium Channel Subunit Function Increases the Susceptibility for Diabetes. Diabetes 66, 897-907, doi:10.2337/db16-0336 (2017)
https://www.ncbi.nlm.nih.gov/pubmed/28115397
8. Tuluc, P., Yarov-Yarovoy, V., Benedetti, B. & Flucher, B. E. Molecular Interactions in the Voltage Sensor Controlling Gating Properties of CaV Calcium Channels. Structure 24, 261-271, doi:10.1016/j.str.2015.11.011 (2016)
https://www.ncbi.nlm.nih.gov/pubmed/26749449
9. Ortner, N. J., Bock, G., Vandael, D. H., Mauersberger, R., Draheim, H. J., Gust, R., Carbone, E., Tuluc, P. & Striessnig, J. Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators. Nat Commun 5, 3897, doi:10.1038/ncomms4897 (2014)
https://www.ncbi.nlm.nih.gov/pubmed/24941892
10. Azizan, E. A., Poulsen, H., Tuluc, P., Zhou, J., Clausen, M. V., Lieb, A., Maniero, C., Garg, S., Bochukova, E. G., Zhao, W., Shaikh, L. H., Brighton, C. A., Teo, A. E., Davenport, A. P., Dekkers, T., Tops, B., Kusters, B., Ceral, J., Yeo, G. S., Neogi, S. G., McFarlane, I., Rosenfeld, N., Marass, F., Hadfield, J., Margas, W., Chaggar, K., Solar, M., Deinum, J., Dolphin, A. C., Farooqi, I. S., Striessnig, J., Nissen, P. & Brown, M. J. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 45, 1055-1060, doi:10.1038/ng.2716 (2013)
https://www.ncbi.nlm.nih.gov/pubmed/23913004
11. Tuluc, P., Molenda, N., Schlick, B., Obermair, G. J., Flucher, B. E. & Jurkat-Rott, K. A CaV1.1 Ca2+ channel splice variant with high conductance and voltage-sensitivity alters EC coupling in developing skeletal muscle. Biophys J 96, 35-44, doi:10.1016/j.bpj.2008.09.027 (2009)
https://www.ncbi.nlm.nih.gov/pubmed/19134469
12. Tuluc, P., Kern, G., Obermair, G. J. & Flucher, B. E. Computer modeling of siRNA knockdown effects indicates an essential role of the Ca2+ channel alpha2delta-1 subunit in cardiac excitation-contraction coupling. Proc Natl Acad Sci U S A 104, 11091-11096, doi:10.1073/pnas.0700577104 (2007)
https://www.ncbi.nlm.nih.gov/pubmed/17563358
Full publication list (Pubmed search)