Physiology and Pharmacology

Nikolai N. Modyanov, Ph.D., D.Sc.

Professor

Telephone: (419) 383-4182, 383-4065, 383-4456
FAX: (419) 383-2871

e-mail: Nikolai.Modyanov@utoledo.edu

Education
M.S. , Organic Chemistry, 1967, Lomonosov Moscow State University, Moscow, Russia
Ph.D. , Bioorganic Chemistry, 1973, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry , Moscow, Russia
D.Sc. Chemistry,1987 , Russian Academy of Sciences., Moscow, Russia

Appointments
Staff Reseacher, Department of Protein Chemistry, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia 1970-1973
Senior Scientist, Department of Protein Chemistry, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia 1973-1979
Principal Investigator, Department of Protein Chemistry, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia 1979-1986
Professor, Head of Laboratory of Membrane Biochemistry, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia 1986-1994
Visiting Professor, Department of Biochemistry of Swiss Federal Institute of Technology, , Zurich, Switzerland,1/1/1993 -12/31/1993
Visiting Professor, Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland 1/1/1994 -6/30/1994
Professor, Department of Pharmacology, Medical College of Ohio, Toledo, OH 1994-2005
Professor, Department of Physiology and Pharmacology, The University of Toledo College of Medicine, Toledo, OH 2006-present  

Research Interests
For more than 30 years research in my lab was focused on the molecular aspects of ion transport across biological membranes, and primarily on the structure-function relationship of the ion-transporting ATPases that are receptors for cardiotonic drugs (Na,K-ATPase) and antiulcer drugs (H,K-ATPase). Together with colleagues we determined the complete primary structure of both subunits of Na,K-ATPase and discovered family of closely related human genes encoding different X,K-ATPases.  One of these genes (ATP1AL1) was shown to encode a catalytic subunit of a hitherto unknown human nongastric H,K-ATPase, which is a new type of human receptor for cardiac glycosides.

New direction of our research resulted in discovery of the unique BetaM proteins encoded by ATP1B4 genes, members of X,K-ATPase gene family. We determined that ATP1B4 genes represent a rare instance of orthologous vertebrate gene co-option that created fundamental changes in the physiological roles and functional properties of the encoded proteins. In lower vertebrates BetaM is a subunit of Na,K-ATPase. In placental mammals BetaM-proteins lost their ancestral functions and acquired entirely new functions as proteins in the inner nuclear membrane of heart and skeletal muscle, which regulate gene expression and signal transduction acting specifically during a critical period of perinatal development and adult muscle regeneration.

These findings indicate that placental mammals should have a hitherto unknown physiologically important necessity, which did require evolutionary forces to trigger co-option of the X-chromosome gene ATP1B4 and fundamental changes in the functional properties of the BetaM proteins.

To better understand the physiological role of the mammalian BetaM, we developed Atp1b4 knockout mouse model and determined that BetaM deficiency sharply decreased level of expression of a major myogenic regulatory factor MyoD and slow down mouse general body development and growth. Moreover, the survival rate of Atp1b4-/Y males and homozygous Atp1b4-/- females is significantly lower than that of male wild type and heterozygous female littermates, respectively.

Most importantly, Atp1b4 knockout males, which survived to adulthood, upon feeding by a high-fat diet showed far less weight gain, are resistant to  diet-induced obesity, exhibit enhanced insulin sensitivity and improved glucose tolerance compared with wild type littermates. Studies on the molecular basis of these beneficial effects of BetaM ablation on dietary fat metabolism are now in progress.

Selected Recent Publications
Pestov, N., Adams, G., Shakhparonov, M., and Modyanov, N. (1999) Identification of a novel gene of the XK-ATPase b-subunit family that is predominantly expressed in skeletal and heart muscles. FEBS Lett. 456:243-248.

Crambert, G., Hasler, U., Beggah, A.T., Yu, C.L., Modyanov, N.N., Horisberger, J.D., Lelievre, L., and Geering, K. (2000) Transport and pharmacological properties of nine different human Na,K-ATPase isozymes. J. Biol. Chem. 275:1976-1986.

Pestov, N.B., Korneenko, T.V., Zhao, H., Adams, G., Shakhparonov, M.I., and Modyanov, N.N. (2000) Immunochemical demonstration of a novel b-subunit isoform of X,K-ATPase in human skeletal muscle. Biochem. Biophys. Res. Commun. 277:430-435.

Pestov, N.B., Korneenko, T.V., Zhao, H., Adams, G., Kostina, M.B., Shakhparonov, M.I., and Modyanov, N.N. (2001) The bm protein, a member of the X,K-ATPase b-subunits family, is located intracellularly in pig skeletal muscle. Arch. Biochem. Biophys. 396:80-88.

Pestov, N., Korneenko, T., Adams, G., Tillekeratne, M., Shakhparonov, M., and Modyanov, N. (2002) Nongastric H, K-ATPase in rodent prostate:lobe-specific expression and apical localization. Am.J.Physiol. 282 :C907-916.

Ivanov, A., Modyanov, N.N., and Askari, A. (2002) Role of the self-association of b subunits in the oligomeric structure of Na+/K+-ATPase. Biochem. J. 364:293-299.

Crambert, G., Beguin, P., Pestov, N.B., Modyanov, N.N., and Geering, K. (2002) bm, a structural member of the X,K-ATPase b subunit family, resides in the ER and does not associate with any known X,K-ATPase a subunit. Biochemistry 41:6723-6733.

Crambert, G., Horisberger, J-D., Modyanov, N.N., and Geering, K. (2002) Human nongastric H+-K+-ATPase: transport properties of ATP1al1 assembled with different b-subunits. Am. J. Physiol. 283:C305-C314.

Pestov NB, Crambert G, Zhao H, Korneenko TV, Shakhparonov MI, Geering K, Modyanov NN (2003) The muscle-specific beta m protein is functionally different from other members of the X,K-ATPase beta-subunit family Ann. N.Y. Acad. Sci. 986:304-305

Zhao, H., Pestov, N.B., Korneenko, T.V., Shakhparonov, M.I., and Modyanov, N.N. (2004) Accumulation of beta(m), a structural member of X,K-ATPase beta-subunit family, in nuclear envelopes of perinatal myocytes. Am. J. Physiol. Cell. Physiol. 286:C757-C767.

Pestov, N.B., Korneenko, T.V., Radkov, R., Zhao, H., Shakhparonov, M.I., and Modyanov, N.N. (2004) Identification of the beta-subunit for nongastric H-K-ATPase in rat anterior prostate. Am. J. Physiol. 286:C1229-C1237.

Pestov, N.B., Korneenko, T.V., Shakhparonov, M.I., Shull, G.E., and Modyanov, N.N. (2006) Loss of acidification of anterior prostate fluids in Atp12a-null mutant mice indicates that nongastric H-K-ATPase functions as proton pump in vivo. Am. J. Physiol. Cell. Physiol. 291:C366-C374.

Radkov R, Kharoubi-Hess S, Schaer D, Modyanov NN, Geering K, Horisberger JD. (2007) Role of homologous ASP334 and GLU319 in human non-gastric H,K- and Na,K-ATPases in cardiac glycoside binding. Biochem Biophys Res Commun. 356:142-146

Pestov, N.B., Ahmad, N., Korneenko, T.V., Zhao, H., Radkov, R., Schaer,D., RoyS, BibertS, Geering, K. and Modyanov, N.N. (2007) Evolution of Na,K-ATPase bm-subunit into a co-regulator of transcription in placental mammals. Proc. Natl. Acad. Sci. USA 104:11215-11220.

Pestov, N.B., Zhao, H., Basrur, V., Modyanov N.N. (2011) Isolation and characterization of BetaM protein encoded by ATP1B4--a unique member of the Na,K-ATPase ß-subunit gene family.  Biochem. Biophys. Res. Commun. 412(4):543-548. 

Pestov NB, Dmitriev RI, Kostina MB, Korneenko TV, Shakhparonov MI, Modyanov NN. (2012)  Structural evolution and tissue-specific expression of tetrapod-specific second isoform of secretory pathway Ca(2+)-ATPase.  Biochem Biophys Res Commun. 2012 Jan 27;417(4):1298-1303.

Salhi, A., Lamouroux, C., Pestov, N.B., Modyanov, N.N., Doucet, A. and Crambert, G. (2013) A link between fertility and K+ homeostasis: Role of the renal H,K-ATPase type 2. Pflügers Archiv - European Journal of Physiology 465:1149-1158.

Pestov, N.B., Korneenko, T.V., Shakhparonov, M.I., and Modyanov, N.N. (2013) Postnatal regulation of X, K-ATPases in rat skin and conserved lateroapical polarizaion of Na, K-ATPase in vertebrate epidermis.  Experimental Dermatology 22:423-425.

 

 

 

Last Updated: 6/26/15