This mini-review describes the history of cell volume conferences with the emphasis on the research of cell volume sensitive peptide exocytosis initiated by Prof. Monte A. Greer as well as the recent achievements on the study of the mechanisms of cell volume adjustment and their implications in the regulation of metabolism, gene expression, cell proliferation and death

V. Štrbák

Bulletin of Siberian Medicine

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   8 Бюллетень сибирской медицины, 2013, том 12, № 4, с. 8–12    УДК 576.36.053:005.745 CELL VOLUME CONFERENCES Štrbák, V. Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia  ABSTRACT This mini-review describes the history of cell volume conferences with the emphasis on the research of cell volume sensitive peptide exocytosis initiated by Prof. Monte A. Greer as well as the recent achievements on the study of the mechanisms of cell volume adjustment and their implications in the regulation of metabolism, gene expression, cell proliferation and death. KEY WORDS: history of cell volume conferences. Bulletin of Siberian Medicine, 2013, vol. 12, no. 4, pp. 8–12                 Vladimír Štrbák,  M.D., Doctor of Science Born 1943 in Nimnica, Slovakia Academic degrees: M.D. 1966 Medical faculty Comenius University, Bratislava Ph.D. 1974 Slovak Academy of Sciences, Bratislava D.Sc. 1990 Slovak Academy of Sciences, Bratislava   Current positions: Head of Laboratory of Neurohumoral Regulation, Institute of Experimental Endocrinology, Slovak Academy of Sciences,  Head of the Institute of Pathological Physiology, Medical Faculty of the Slovak Medical University, Bratislava, Slovak Republic Chairman of the Scientific Committee of the Slovak Academy of Sciences for Medical Sciences Visiting profesor, Medical School University in Kragujevac ISP Council member  Organizer and chairman International Symposium on Cell volume and function, 1997 Local Organizing Committee of the Joint Conference of the Slovak Physiological Society, the Physiological Society and Federation of the European Physiological Societies, Bratislava, 2007 Five International symposia on Hormones in Milk, President of International Organizing Committee: the First  Joint Conference of Physiologists from Central Europe, Piešťany,  2002  Cell swelling-induced peptide exocytosis – how I get engaged In the years 1977–78 I spent postdoctoral fellowship in Oregon Health Sciences University in Portland in laboratory of Prof. Monte A. Greer. During my later visit in 1990 Monte told me about very interesting effect of hyposmolarity on protein and peptide secretion. In early eighties they studied the dynamics of in vitro hormone                               Štrbák Vladimír, e-mail: Vladimir.strbak@savba.sk secretion of adenohypophyseal cells induced by various secretagogues. Accidentally they found unexpected and stricking dose-related stimulation of secretion of LH by dilution of the perfusion medium with distilled water. They had expected that any efflux of hormone induced by dilution of the medium with water would most likely be due to osmotic lysis of the cells. However, repeated hyposmolar stimulation over a 5-hr experimental period produced similar secretory response each time and did not depress the stimulation of thyrotropin (TSH) and prolacti 10TH INTERNATIONAL CONGRESS  “CELL VOLUME REGULATION: NOVEL THERAPEUTIC TARGETS AND PHARMACOLOGICAL APPROACHES”  10th International Congress “Cell Volume Regulation: Novel Therapeutic Targets and Pharmacological Approaches”   Бюллетень сибирской медицины, 2013, том 12, № 4, с. 8–12 9 (PRL) secretion induced by the same dose of thyroliberin (TRH) given at the beginning, middle, and end of the experimental period [1, 2]. Moreover, hyposmolarity simultaneously stimulated secretion of all hormones they had measured (growth hormone, PRL, TSH, luteotropin, adrenocorticotropin). They believed that this interesting effect may be clue to understanding exocytotic process [1]. Later they discovered that similar mechanism inducing insulin release in vitro had been described by Blackard et al. in 1975 [3].   Prof. Monte A. Greer, Oregon Health Sciences University. Pioneer in the field of neuro-endocrine regulation and cell swelling-induced   protein and peptide secretion (exocytosis).  Monte Greer was surprised and disappointed by lack of interest of scientific community in this phenomenon. We started Portland – Bratislava collaboration supported by project of US-Slovak Science and Technology coop-eration program. To break isolation we were looking for groups studying various aspects of cell volume regulation and effects. We contacted Florian Lang, one of the organ-izers of the conference „Interaction of Cell Volume and Cell Function” held in 1990 in Innsbruck and organized with him International symposium „Primary Role of Cell Volume Changes in Controlling Cell Function” in Smolenice Castle, 1997 in Slovakia. Meeting excellent scientists presenting cutting edge results of knowledge has been very important for our further research. Apparently most of participants shared this feelings and a series of special conferences devoted to cell volume in 1–3 years intervals has been held since that time (Table 1). Despite rigorous scientific criticism, atmosphere of all meetings was extremely friendly; full of understanding and mutual support. Cell volume has been appreciated as important field also by Physiological and Pathophysiological world and European societies by organizing cell volume sympo-sia, workshops or sessions as part of program of their con-gresses (Table 2). T a b l e  1  Congresses on Cell Volume 1990  Innsbruck, Austria, “Interaction of Cell Volume and Cell Func-tion”. Organizers: F. Lang, D. Häussinger 1997  Smolenice Castle, Slovakia, “Primary Role of Cell Volume Changes in Controlling Cell Function”.  Organizers: V. Strbak, M.A. Greer, F. Lang 2000  Berlin, Germany, “Cell Volume: Signalling and Regulation”. Organizer: F. Wehner 2001  Queenstown, New Zealand, “Molecular Mechanisms in Cell Volu-me Regulation”. Organizers: J. Leader, J. Bedford, P. Donaldson, E.K. Hoffmann, K. Spring 2003 Dayton, USA, “Cell Volume & Signal Transduction”. Organizers: P. Lauf, N. Adragna 2005 Copenhagen, Denmark, “Cell Volume Control in Health and Disease”. Organizers: E.K. Hoffmann, I.H. Lambert, S.F. Pe-dersen, D. Klaerke, A. Schousboe 2007 Salzburg, Austria, “Cell Volume Control: Functions – Molecules – Interactions”. Organizer: M. Ritter 2009 Okazaki, Japan, Joint Symposium “Physiology of Ion Transport and Cell Volume Regulation”. Organizers: Y. Okada, S. Uchida, H. Sakai 2011 Tubingen, Germany, “Hydration & Cell Volume Regulation – Mechanisms and Regulation”. Organizers: F. Lang, E. Shumilina, H. Osswald Coming conference 2013 Moscow, Russia, August 26–29, “Cell Volume Regulation: Novel Therapeutic Targets & Pharmacological Approaches”. Organizer: Sergei Orlov  T a b l e  2  Symposia and Workshops on Cell Volume as part of program  at International Congresses 2002 Piešťany, Slovakia, February 5–8, 2002, First Joint Conference of Physiologists from Central Europe, Symposium „Cell Volume: Regulation and Function”. Organizer: V. Štrbák 2003 3rd Federation of European Physiological Societies Congress, Nice, France, June 28 – July 3, 2003, Symposium „Cell volume: Regula-tion and Functional Impact”. Organizer: V. Štrbák 2006 Beijing, China, June 28 – July 1, 2006, 5th International Congress of Pathophysiology Symposium “Cell Volume, Physiological and Pathophysiological aspects”. Organizer: V. Štrbák (chairs V. Štrbák and Y. Okada) 2010 Montreal, Canada, September 22–25, 2010, 6th International Congress of Pathophysiology, Workshop, Cell Volume Regulation. Organizer: V. Štrbák. Chairs: V. Štrbák (Bratislava, Slovakia) and S.N. Orlov (Montréal, Canada)  Various functions of cell volume. To survive, cells have to maintain their volume within certain limits. Pro-tective mechanism(s) should have to develop in early forms of life to assure survival in changing environment. Diverse experimental approach revealed that phylogeneti-cally divergent organisms employ uniquely adapted mechanisms of cell volume regulation [4]. Cell volume Štrbák, V. Cell Volume Conferences  10 Бюллетень сибирской медицины, 2013, том 12, № 4, с. 8–12 perturbation elicits a wide array of signaling events, lea-ding to protective and adaptive measures [5–8]. In higher organisms cell volume responses to osmotic challenge are  Conference 2007 in Salzburg, Austria, “Cell Volume Control: Functions – Molecules – Interactions”. Organizer: M. Ritter (in the middle  in blue shirt).   Conference 2009, Okazaki, Japan, August 3–6, 2009, Joint Symposium “Physiology of Ion Transport and Cell Volume Regulation”. Organizers: Y. Okada, S. Uchida, H. Sakai. From the   left Yasunobu Okada, and Else Hoffmann.   Conference 2009, Okazaki, Japan, August 3–6, 2009, Joint Symposium “Physiology of Ion Transport and Cell Volume Regulation”. Organizers: Y. Okada, S. Uchida, H. Sakai. From the   left Vladimir Strbak, Sergei Orlov, Ryszard Grygorczyk. integrated into a signal transduction network regulating various cell functions; it has become evident that cell vol-ume should be considered a second message in the trans-mission of various functions; alterations of cell volume and volume regulatory mechanisms participate in a wide variety of cellular functions [5]:  Metabolism. Cell volume was shown to be important determinant of proteolysis and protein synthesis in the liver. It has been also demonstrated that cell volume changes exerted by hormones and amino acids play a cru-cial role in their role in regulation of hepatic protein me-tabolism [9–11]. Cell volume affects gene expression [5, 12]. Cell volume affects apoptotic death and cell prolifer-ation [13–15]. Cell migration [16]. Cell volume mediates various hormone actions [5, 9–11]. Hydrogel nature of mammalian cytoplasm contributes to osmosensing and extracellular pH sensing [17]. Cell swelling-induced peptide and protein exocyto-sis [18]. More about my favorite issue: Cell swelling-induced peptide and protein exocytosis. Cell swelling induces peptide exocytosis using unique signa- 10th International Congress “Cell Volume Regulation: Novel Therapeutic Targets and Pharmacological Approaches”   Бюллетень сибирской медицины, 2013, том 12, № 4, с. 8–12 11 ling pathway [19]. Hyposmotic-induced secretion in normal cells is not mediated by specific receptors, is independent from extra and intracellular Ca2+-sodium and potassium channels activity, prostaglandins, leukotriens, does not involve cytoskeleton, cAMP generation, phospholipase A2, G proteins, protein kinase C [19–21]. It is promoted by swelling of the secretory vesicles [19]. Resistance to endogenous inhibitors is frequent attribute of this type of secretion [19–21]. Swelling-induced secretion involves also secretory vesicles not involved in conventional stimu-lation [19–22]. Hyposmosis-induced insulin secretion is more sensitive to high cellular cholesterol than conven-tional one suggesting substantial difference between mechanisms [22]. Participation of sequential exocytosis as dominating mechanism in swelling-induced exocytosis is hypothesized [19–22]. Signaling and response in tumor cells often differs from native cells and varies markedly between cell lines [19].  Pathogenetic implications: cell swelling could be in-volved in alcohol induced hypoglycemia in diabetic pa-tients and release of peptides from pituitary and neurons [19, 23]. Swelling-induced products could be mediators of ischemic preconditioning involved also in protection of diabetic heart. Swelling-induced exocytosis is an ancient mechanism generally present in cells; in cells engaged in water and salt regulation is covered by specific response mediated by specific signaling [24, 25]. Disturbance of specific response leads to swelling-induced – inappropriate secretion of antidiuretic hormone – SIADH [19, 23, 2]. Exocytosis of intravesicular material has been supposed to help a swollen cell to meet the challenge by expanding the plasmalemma through the fusion with vesicular membrane [18]. Surprisingly, in mammalian cells significant end membrane insertion was observed only during extreme swelling [26].  Recently an interesting hypothesis was published by E. Mariman [27]: during weight loss and shrinkage of cells, adipocytes will automatically change their adipokine secretion profile. Model is based on the fact that chronic change of cell volume results in long lasting stimulation or inhibition of secretion (secretion of leptin and other proinflammatory adipokines is positively related to adipo-cyte volume). Changed secretion profile of adipokines is a strong regulatory factor promoting regain of body weight. This is interesting view on the possible role of chronic change of cell volume in the pathogenesis of obesity [28]. I believe that cell volume field has big potential lea-ding to important discoveries to motivate organization of many further conferences with exciting program. Acknowledgements This research was supported by APVV 0235-06, APVV-0253-10, APVV 0486-10, Chicago Diabetes Pro-ject and VEGA 2/0132/12. References 1. Greer M.A., Greer S.E., Opsahl Z., McCafferty L., Maruta S. Hyposmolar stimulation of in vitro pituitary secretion of lu-teinizing hormone: a potential clue to the secretory process. Endocrinology, 1983, 113, pp. 1531–1533.  2. Greer M.A., Greer S.E., Opsahl Z., Maruta S. Comparison of hyposmolar and hyperosmolar effects on in vitro luteinizing hormone secretion by anterior pituitary cells. Proc. Soc. Exp. Biol. Med., 1985, 178, pp. 24–28.  3. Blackard W.G., Kikuchi M., Rabinovitch A., Renold A.E. An effect of hyposmolarity on insulin release in vitro. Am. J. Physiol., 1975, 228, pp. 706–713. 4. Chamberlin M.E., Strange K. Anisosmotic cell volume regu-lation: a comparative view. Am. J. Physiol., 1989, 257, C159–173. 5. Lang F., Busch G.L., Ritter M., Völkl H., Waldegger S., Gulbins E., Häussinger D. Functional significance of cell volume regulatory mechanisms. Physiol Rev., 1998, 78 (1), pp. 247–306. 6. Okada Y., Hazama A., Yuan W.L. Stretch-induced activa-tion of Ca2+-permeable ion channels is involved in the vo-lume regulation of hypotonically swollen epithelial cells. Neurosci. Res. Suppl., 1990, 12, S5–13. 7. Wehner F., Olsen H., Tinel H., Kinne-Saffran E., Kinne R.K.H. Cell volume regulation: osmolytes, osmolyte transport, and signal transduction. Rev. Physiol. Biochem. Pharmacol., 2003, 148, pp. 1–80. 8. Hoffmann E.K., Lambert I.H., Pedersen S.F. Physiology of Cell Volume Regulation in Vertebrates. Physiol. Rev., 2009, 89, pp. 193–277. 9. Häussinger D., Hallbrucker C., vom Dahl S., Decker S., Schweizer U., Lang F., Gerok W. Cell volume is a major de-terminant of proteolysis control in liver. FEBS Lett., 1991, 20, 283 (1), pp. 70–2. 10. Stoll B., Gerok W., Lang F., Häussinger D. Liver cell vo-lume and protein synthesis. Biochem. J., 1992, 287 (Pt. 1), pp. 217–22. 11. Häussinger D., Lang F. Cell volume and hormone action. Trends Pharmacol Sci., 1992, 13 (10), 371–373. Review. 12. Waldegger S., Lang F. Cell volume and gene expression. J. Membr. Biol., 1998, 162 (2), 95–100. Review. 13. Lang F., Uhlemann A.C., Lepple-Wienhues A., Szabo I., Siemen D., Nilius B., Gulbins E. Cell volume regulatory mechanisms in apoptotic cell death. Herz., 1999, 24 (3), 232–5. Review.  14. Lang F., Ritter M., Gamper N., Huber S., Fillon S., Tanneur V., Lepple-Wienhues A., Szabo I., Gulbins E. Cell volume in the regulation of cell proliferation and apoptotic cell death. Cell Physiol Biochem., 2000, 10 (5–6), 417–28. Review. 15. Okada Y., Maeno E. Apoptosis, cell volume regulation and volume-regulatory chloride channel. Comp. Biochem. Physiol. A Mol. Integr. Physiol., 2001, 130 (3), 377–83. Review. 16. Jakab M., Ritter M. Cell volume regulatory ion transport in the regulation of cell migration. Contrib. Nephrol., 2006, 152, pp. 161–180.  17. Fels J., Orlov S.N., Grygorczyk R. The hydrogel nature of mammalian cytoplasm contributes to osmosensing and ex-tracellular pH sensing. Biophys. J., 2009, 96 (10), pp. 4276–4285. 18. Strbak V., Greer M.A. Regulation of hormone secretion by acute cell volume changes: Ca2+-independent hormone secre-tion. Review. Cell. Physiol. Biochem., 2000, 10, pp. 393–Štrbák, V. Cell Volume Conferences  12 Бюллетень сибирской медицины, 2013, том 12, № 4, с. 8–12 402. 19. Strbak V. Cell swelling-induced peptide hormone secretion. Cell Physiol. Biochem., 2011, 28, pp. 1155–1168. 20. Najvirtova M., Greer S.E., Greer M.A., Baqi L., Benicky J., Strbak V. Cell Volume Induced Hormone Secretion: Studies on Signal Transduction and Specificity. Cell Physiol. Biochem., 2003, 13, pp. 113–122. 21. Bacová Z., Benický J., Lukyanetz E.E., Lukyanets I.A., Štrbák V. Different signaling pathways involved in glu-cose and cell swelling-induced insulin secretion by rat pancreatic islets in vitro. Cell Physiol. Biochem., 2005, 16, pp. 9–68. 22. Bacová Z., Hafko R., Orečná M., Kohút P., Hapala I., and Strbák V. Effect of Cellular Cholesterol Changes on Insulin Secretion by Tumor Cell Lines. Medicinal Chemistry, 2012, 8, pp. 65–71. 23. Strbak V. Cell volume and Peptide Hormone secretion. Contrib. Nephrol., 2006, 152, pp. 210–220. 24. Bacová Z., Kiss A., Jamal B., Payer J Jr., Štrbák V. The ef-fect of swelling on TRH and oxytocin secretion from hypo-thalamic structures. Cell Mol. Neurobiol., 2006, 26, pp. 1047–1055. 25. Štrbák V. Neurons and cell swelling-induced peptide hor-mone secretion. In: Kamkin A. and Kiseleva I. (eds): Mecha-nosensitivity of the nervous system, Springer Science + Bussiness Media B.V. 2009, pp. 69–85. 26. Groulx N., Boudreault F., Orlov S.N., Grygorczyk R. Mem-brane reserves and hypotonic cell swelling. J. Membr. Biol., 2006, 214 (1), pp. 43–56.  27. Mariman E.C.M. An adipobiological model for weight re-gain after weight loss. Review. Adipobiology., 2011, 3, pp. 9–16,  28. Štrbák V. Both acute and chronic cell volume changes are engaged in regulation of adipocyte functions. Commentary. 2011, 3, pp. 17–18.  Поступила в редакцию 04.06.2013 г. Утверждена к печати 10.06.2013 г.  Štrbák Vladimír (), M.D., DrSc., Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.  Štrbák Vladimír, e-mail: Vladimir.strbak@savba.sk   

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