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Calcium signaling in development and disease

thesis
posted on 2024-09-02, 23:57 authored by Marie Karlsson

The calcium ion (Ca2+) is a highly versatile signaling messenger involved in a diverse range of physiological processes such as gene transcription/expression, proliferation, differentiation and cell death. Intracellular Ca2+ signals are generated through a 10 000 – 20 000 fold gradient across the cell membrane and via release from the external milieu and/or internal Ca2+ stores. Cells have a unique signaling toolkit to control Ca2+ homeostasis including a selection of ion channels, pumps, exchangers and Ca2+ binding proteins.

We have reported that ouabain, an endogenous steroid hormone and ligand to the Na+,K+-ATPase, can trigger dendritic growth in cortical neurons through signal transduction. This involves a Ca2+-dependent transcriptional program regulated by CREB and CRE-mediated gene activation, primarily regulated through Ca2+/calmodulin-dependent protein kinases. The process also includes Ca2+ oscillations and phosphorylation of mitogen-activated protein kinases (ERK 1/2). These data suggest a novel role for Na+,K+-ATPase and Ca2+ in dendritic growth during development.

Previous work has shown that treatment with protein kinase C (PKC) inhibitors results in a prolonged Ca2+ increase leading to calpain activation and release of apoptosis-inducing factor (AIF). We have demonstrated that hyperpolarization- activated cyclic nucleotide-gated (HCN) channel 2 is responsible for the Ca2+ influx. The influx is regulated via dephosphorylation of a residue in the intracellular C- terminal. This data shows a novel role for HCN channel 2 in cell death and a new possible drug target.

Bladder cancer is overall one of the ten most common cancers. We have shown that treatment with Bacillus Calmette-Guerin (BCG), currently the most effective intravesical agent against bladder cancer, induces an intracellular Ca2+ increase and reduces cell proliferation in urinary bladder cancer (T24) cells. Store depletion by SERCA inhibition blocked the BCG-triggered signal, thereby suggesting a role of the endoplasmic reticulum as a Ca2+ source. This signaling event was dependent on phospholipas C since pharmacological inhibition or small interference RNA-mediated gene silencing abolished the response. Finally EdU incorporation revealed that BCG- controlled cell proliferation was mediated via a Ca2+- and PLC-dependent signaling cascade.

In summary this thesis presents three studies highlighting three different roles for Ca2+ signaling. They show that Ca2+ signaling is involved in processes critical for cell differentiation, cell proliferation, and cell death, three aspects highly coordinated with development and disease.

List of scientific papers

I. Desfrere L, Karlsson M, Hiyoshi H, Malmersjö S, Nanou E, Estrada M, Miyakawa A, Lagercrantz H, El Manira A, Lal M, Uhlén P (2009). Na,KATPase signal transduction triggers CREB activation and dendritic growth. Proc Natl Acad Sci U S A. 106(7), 2212-7.
https://doi.org/10.1073/pnas.0809253106

II. Norberg E, Karlsson M, Korenovska O, Szydlowski S, Silberberg G, Uhlén P, Orrenius S, Zhivotovsky B (2010). Critical role for hyperpolarizationactivated cyclic nucleotide-gated channel 2 in the AIF-mediated apoptosis. EMBO J. 29(22), 3869-78.
https://doi.org/10.1038/emboj.2010.253

III. Karlsson M, Ibarra C, Kjällquist U, Zajac P, Lundgren K, Kaba R, Bavand-Chobot N, Linnarsson S, Wiklund P, Miyakawa A, and Uhlén P. Bacillus Calmette-Guerin (BCG) Triggers PLC-Dependent Ca2+ Signaling in Bladder Cancer Cells. [Manuscript]

History

Defence date

2011-02-04

Department

  • Department of Medical Biochemistry and Biophysics

Publisher/Institution

Karolinska Institutet

Publication year

2011

Thesis type

  • Doctoral thesis

ISBN

978-91-7457-211-7

Number of supporting papers

3

Language

  • eng

Original publication date

2011-01-13

Author name in thesis

Karlsson, Marie

Original department name

Department of Medical Biochemistry and Biophysics

Place of publication

Stockholm

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