Calcium signaling in development and disease

<p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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.</p><h3>List of scientific papers</h3><p>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. <br><a href="https://doi.org/10.1073/pnas.0809253106">https://doi.org/10.1073/pnas.0809253106</a><br><br> </p><p>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. <br><a href="https://doi.org/10.1038/emboj.2010.253">https://doi.org/10.1038/emboj.2010.253</a><br><br> </p><p>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]</p>