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Physiology of Calcium Channels / Neuro-Muscular Physiology

Research: Structure and Function of Voltage-Gated Calcium Channels in Excitable Cells

Voltage-gated calcium channels are key regulators of vital cell functions such as contraction of heart and skeletal muscles, secretion of hormones and neurotransmitters, or the regulation of gene expression. Voltage-gated calcium channels function by opening their calcium-selective channel pore in response to changes of the membrane potential. The resulting influx of calcium ions into the cell depolarizes the plasma membrane and the transient rise in the cytoplasmic calcium concentration serves as second messenger activating a multitude of signaling pathways and cell functions. Our laboratory uses state-of-the-art molecular genetics, cell biology, electrophysiology, and high-resolution microscopy approaches to study calcium channel functions in muscle and nerve cells.

Excitation-Contraction Coupling: In skeletal and cardiac muscle voltage-gated calcium channels convert the incoming electrical signal into calcium release from intracellular stores that in turn triggers contraction. Our research emphasis on skeletal muscle calcium channels led to the identification of hitherto unnoticed channel isoforms and revealed molecular mechanisms involved in the targeting and assembly of the calcium channel subunits in the triad junction. Structure-function studies revealed the molecular basis of the unique biophysical properties of the skeletal muscle calcium channel.

Synapse formation and synaptic plasticity: In synapses presynaptic calcium channels control the release of neurotransmitter in response to action potentials and postsynaptic calcium channels are involved in mechanisms of synaptic plasticity. Research in our laboratory is concerned with the assembly and composition of synaptic calcium channel complexes and the contribution of specific channel subunits to the development and function of synapses. Recent findings revealed a role of an auxiliary calcium channel subunit in the transcriptional regulation of other synaptic ion channel genes.

Calcium channels and disease: The essential functions of voltage-gated calcium channels in important physiological processes are mirrored by a broad range of disorders related to aberrant calcium channel functions. Channelopathies studied in our laboratory include dystrophic myotonia, cerebellar ataxia, and diabetes.

 

group1Joint research groups of Bernhard Flucher and Gerald Obermair (link)

 

Ongoing Research

  • The role of calcium channels in acetylcholine receptor pre-patterning during neuromuscular junction development
  • Expression and function of the skeletal muscle calcium channel splice variant CaV1.1DE29.
  • The molecular mechanisms regulating voltage-sensitivity of CaV1 calcium channels.
  • Bernhard Flucher heads the FWF-funded PhD program Molecular Cellular Biology & Oncology (MCBO)

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News

Fürstentum Liechtenstein Award for Marta Campiglio, article at mypoint, 2019  Anklick_Icon

 

Latest Publications

 

Book_Publication_IconEl Ghaleb Y, Campiglio M, Flucher BE. (2019) Correcting the R165K substitution in the first voltage-sensor of CaV1.1 right-shifts the voltage-dependence of skeletal muscle calcium channel activation. Channels (Austin). 2019 Dec;13(1):62-71. doi: 10.1080/19336950.2019.1568825. https://www.ncbi.nlm.nih.gov/pubmed/30638110

 

Book_Publication_IconFlucher BE, Campiglio M. (2019) STAC proteins: The missing link in skeletal muscle EC coupling and new regulators of calcium channel function. Biochim Biophys Acta Mol Cell Res. 2019 Jul;1866(7):1101-1110. doi: 10.1016/j.bbamcr.2018.12.004. Epub 2018 Dec 10. Review. https://www.ncbi.nlm.nih.gov/pubmed/30543836

 

Book_Publication_IconCampiglio M, Kaplan MM, Flucher BE. (2018) STAC3 incorporation into skeletal muscle triads occurs independent of the dihydropyridine receptor. J Cell Physiol. 2018 Dec;233(12):9045-9051. doi: 10.1002/jcp.26767. Epub 2018 Aug 2. https://www.ncbi.nlm.nih.gov/pubmed/30071129

 

Book_Publication_IconCosté de Bagneaux P, Campiglio M, Benedetti B, Tuluc P, Flucher BE. (2018) Role of putative voltage-sensor countercharge D4 in regulating gating properties of CaV1.2 and CaV1.3 calcium channels. Channels (Austin). 2018;12(1):249-261. doi: 10.1080/19336950.2018.1482183. https://www.ncbi.nlm.nih.gov/pubmed/30001160

 

Book_Publication_IconKaplan MM, Sultana N, Benedetti A, Obermair GJ, Linde NF, Papadopoulos S, Dayal A, Grabner M, Flucher BE. (2018) Calcium Influx and Release Cooperatively Regulate AChR Patterning and Motor Axon Outgrowth during Neuromuscular Junction Formation. Cell Rep. 2018 Jun 26;23(13):3891-3904. doi: 10.1016/j.celrep.2018.05.085. https://www.ncbi.nlm.nih.gov/pubmed/29949772

 

Book_Publication_IconCampiglio M, Costé de Bagneaux P, Ortner NJ, Tuluc P, Van Petegem F, Flucher BE. (2018) STAC proteins associate to the IQ domain of CaV1.2 and inhibit calcium-dependent inactivation. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):1376-1381. doi: 10.1073/pnas.1715997115. Epub 2018 Jan 23. https://www.ncbi.nlm.nih.gov/pubmed/29363593

 

Book_Publication_IconWong King Yuen SM, Campiglio M, Tung CC, Flucher BE, Van Petegem F. (2017) Structural insights into binding of STAC proteins to voltage-gated calcium channels. Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):E9520-E9528. doi: 10.1073/pnas.1708852114. Epub 2017 Oct 23. https://www.ncbi.nlm.nih.gov/pubmed/29078335

 

Book_Publication_IconFindeisen, F., Campiglio, M., Jo, H., Rumpf, C.H., Pope, L., Abderemane-Ali, F., Rossen, N.D., Flucher, B.E., DeGrado, W.F., and Minor, D.L. Jr (2017) Stapled voltage-gated calcium channel (CaV) α-interaction domain (AID) peptides act as selective protein-protein interaction inhibitors of CaV function. ACS Chem. Neurosci., 2017 Mar 17. doi: 10.1021/acschemneuro.6b00454. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28278376

 

Book_Publication_IconMastrolia, V., Flucher, S.M., Obermair, G.J., Drach, M., Hofer, H., Renström, E., Schwartz, A., Striessnig, J., Flucher, B.E., and Tuluc, P. (2017) Loss of α2δ-1 calcium channel subunit function increases the susceptibility for diabetes. Diabetes, 2017 Jan 23. pii: db151349. doi: 10.2337/db16-0336. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28115397

 

Book_Publication_IconCampiglio, M. and Flucher, B.E. (2017) STAC3 stably interacts through its C1 domain with CaV1.1 in skeletal muscle triads. Sci. Rep., 7:41003. doi: 10.1038/srep41003; https://www.ncbi.nlm.nih.gov/pubmed/28112192

 

Book_Publication_IconFlucher, B.E. and Tuluc, P. (2017) How and why are calcium currents curtailed in the skeletal muscle voltage-gated calcium channels? J. Physiol., 595:1451-1463. https://www.ncbi.nlm.nih.gov/pubmed/27896815

 



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