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      Protein Kinase CK2 Controls Ca V2.1-Dependent Calcium Currents and Insulin Release in Pancreatic β-cells

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          Abstract

          The regulation of insulin biosynthesis and secretion in pancreatic β-cells is essential for glucose homeostasis in humans. Previous findings point to the highly conserved, ubiquitously expressed serine/threonine kinase CK2 as having a negative regulatory impact on this regulation. In the cell culture model of rat pancreatic β-cells INS-1, insulin secretion is enhanced after CK2 inhibition. This enhancement is preceded by a rise in the cytosolic Ca 2+ concentration. Here, we identified the serine residues S 2362 and S 2364 of the voltage-dependent calcium channel Ca V2.1 as targets of CK2 phosphorylation. Furthermore, co-immunoprecipitation experiments revealed that Ca V2.1 binds to CK2 in vitro and in vivo. Ca V2.1 knockdown experiments showed that the increase in the intracellular Ca 2+ concentration, followed by an enhanced insulin secretion upon CK2 inhibition, is due to a Ca 2+ influx through Ca V2.1 channels. In summary, our results point to a modulating role of CK2 in the Ca V2.1-mediated exocytosis of insulin.

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          One-thousand-and-one substrates of protein kinase CK2?

          Flavio Meggio, Lorenzo Pinna, Frank Rozsa (2003)
          CK2 (formerly termed "casein kinase 2") is a ubiquitous, highly pleiotropic and constitutively active Ser/Thr protein kinase whose implication in neoplasia, cell survival, and virus infection is supported by an increasing number of arguments. Here an updated inventory of 307 CK2 protein substrates is presented. More than one-third of these are implicated in gene expression and protein synthesis as being either transcriptional factors (60) or effectors of DNA/RNA structure (50) or translational elements. Also numerous are signaling proteins and proteins of viral origin or essential to virus life cycle. In comparison, only a minority of CK2 targets (a dozen or so) are classical metabolic enzymes. An analysis of 308 sites phosphorylated by CK2 highlights the paramount relevance of negatively charged side chains that are (by far) predominant over any other residues at positions n+3 (the most crucial one), n+1, and n+2. Based on this signature, it is predictable that proteins phosphorylated by CK2 are much more numerous than those identified to date, and it is possible that CK2 alone contributes to the generation of the eukaryotic phosphoproteome more so than any other individual protein kinase. The possibility that CK2 phosphosites play some global role, e.g., by destabilizing alpha helices, counteracting caspase cleavage, and generating adhesive motifs, will be discussed.
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            RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction.

            Pascal S Kaeser, Lunbin Deng, Yun Wang … (2011)
            At a synapse, fast synchronous neurotransmitter release requires localization of Ca(2+) channels to presynaptic active zones. How Ca(2+) channels are recruited to active zones, however, remains unknown. Using unbiased yeast two-hybrid screens, we here identify a direct interaction of the central PDZ domain of the active-zone protein RIM with the C termini of presynaptic N- and P/Q-type Ca(2+) channels but not L-type Ca(2+) channels. To test the physiological significance of this interaction, we generated conditional knockout mice lacking all multidomain RIM isoforms. Deletion of RIM proteins ablated most neurotransmitter release by simultaneously impairing the priming of synaptic vesicles and by decreasing the presynaptic localization of Ca(2+) channels. Strikingly, rescue of the decreased Ca(2+)-channel localization required the RIM PDZ domain, whereas rescue of vesicle priming required the RIM N terminus. We propose that RIMs tether N- and P/Q-type Ca(2+) channels to presynaptic active zones via a direct PDZ-domain-mediated interaction, thereby enabling fast, synchronous triggering of neurotransmitter release at a synapse. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells.

              Gaelle Chaffard, Blanca Rubi, Pierre Maechler … (2004)
              Rat insulinoma-derived INS-1 cells constitute a widely used beta-cell surrogate. However, due to their nonclonal nature, INS-1 cells are heterogeneous and are not stable over extended culture periods. We have isolated clonal INS-1E cells from parental INS-1 based on both their insulin content and their secretory responses to glucose. Here we describe the stable differentiated INS-1E beta-cell phenotype over 116 passages (no. 27-142) representing a 2.2-yr continuous follow-up. INS-1E cells can be safely cultured and used within passages 40-100 with average insulin contents of 2.30 +/- 0.11 microg/million cells. Glucose-induced insulin secretion was dose-related and similar to rat islet responses. Secretion saturated with a 6.2-fold increase at 15 mm glucose, showing a 50% effective concentration of 10.4 mm. Secretory responses to amino acids and sulfonylurea were similar to those of islets. Moreover, INS-1E cells retained the amplifying pathway, as judged by glucose-evoked augmentation of insulin release in a depolarized state. Regarding metabolic parameters, INS-1E cells exhibited glucose dose-dependent elevations of NAD(P)H, cytosolic Ca(2+), and mitochondrial Ca(2+) levels. In contrast, mitochondrial membrane potential, ATP levels, and cell membrane potential were all fully activated by 7.5 mm glucose. Using the perforated patch clamp technique, 7.5 and 15 mm glucose elicited electrical activity to a similar degree. A K(ATP) current was identified in whole cell voltage clamp using diazoxide and tolbutamide. As in native beta-cells, tolbutamide induced electrical activity, indicating that the K(ATP)conductance is important in setting the resting potential. Therefore, INS-1E cells represent a stable and valuable beta-cell model.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 30 June 2020
                Publication date Collection: July 2020
                Volume: 21
                Issue: 13
                Electronic Location Identifier: 4668
                Affiliations
                [1 ]Department of Medical Biochemistry and Molecular Biology, Saarland University, Kirrberger Str., bldg. 44, D-66424 Homburg, Germany; rebecca.gross@ 123456hotmail.de (R.S.); mathias.montenarh@ 123456uks.eu (M.M.)
                [2 ]Department of Experimental and Clinical Pharmacology and Toxicology, Saarland University Kirrberger Str., bldg. 45-46, D-66424 Homburg, Germany; stephan.philipp@ 123456uks.eu (S.E.P.); AlexBecker5683@ 123456hotmail.de (A.B.)
                [3 ]Institute for Clinical & Experimental Surgery, Saarland University Kirrberger Str., bldg. 65, D-66424 Homburg, Germany; lisa.nalbach@ 123456uks.eu (L.N.); emmanuel.ampofo@ 123456uks.eu (E.A.)
                Author notes
                [* ]Correspondence: claudia.goetz@ 123456uks.eu
                Author information
                https://orcid.org/0000-0003-1959-9167
                https://orcid.org/0000-0002-1886-5657
                https://orcid.org/0000-0001-7115-0485
                Article
                Publisher ID: ijms-21-04668
                DOI: 10.3390/ijms21134668
                PMC ID: 7370021
                PubMed ID: 32630015
                SO-VID: d994a84c-0f03-4268-b969-badf1cf9a9f8
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 14 May 2020
                Date accepted : 26 June 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: ck2,ins-1,cx-4945,cav2.1,insulin secretion
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: ck2, ins-1, cx-4945, cav2.1, insulin secretion

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