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Department of Pharmacology

Department of Pharmacology

Donald M. Bers Ph.D.

Donald M. Bers Ph.D.

Professor and Chair
Ph.D., University of California, Los Angeles, CA
(530) 752-6517
e-mail

Recent/Current Research Funding

National Institutes of Health

Fondation Leducq

Graduate Group Affiliations

 

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Research Interests

Cellular and molecular factors involved in the control of cardiac muscle contraction.

Research Synopsis

Dr. Bers research program focuses on cellular and molecular factors involved in the control of cardiac muscle contraction, particularly as modulated by intracellular [Ca]. Cellular Ca regulates contraction and is in a dynamic, yet delicate balance in cardiac muscle cells.

Variations in this Ca balance are crucial to physiological and pharmacological mechanisms that increase cardiac contraction (i.e., with inotropic agents such as digitalis). Disturbance of this balance also can be responsible for pathological states (e.g. incomplete relaxation between beats and the generation of cardiac arrhythmias). Thus, detailed study of cellular Ca regulation is central to understanding cardiac muscle contraction.

At each beat, Ca enters the cell via Ca channels (ICa) and via Na/Ca exchange. Some of the Ca that enters the cell triggers the release of additional Ca from the sarcoplasmic reticulum (SR). Ca from these sources binds to the myofilaments (MF) activating contraction.

During relaxation, Ca is removed from the cytoplasm by: (1) the SR Ca-ATPase (pumping Ca back into the SR), (2) the sarcolemmal Na/Ca exchange, (3) the sarcolemmal Ca-ATPase pump (pumping Ca back out of the cell), and (4) transport into mitochondria (where it modifies ATP production). Donald Bers' research involves the cellular Ca that regulates contraction and is in a dynamic, yet delicate balance in cardiac muscle cells.

It is the study of these Ca transport systems themselves and their interplay with each other that allows us to develop a fuller understanding of how the heart works and is regulated. For example, recent studies from the lab have clarified quantitatively how the four systems above compete to reduce [Ca]i during relaxation.

Study of these systems entails a number of modern physiological and biophysical approaches. Ca channels (and Na/Ca exchange)are studied with patch-clamp techniques in both the single channel and whole cell mode. Intracellular [Ca] is measured in single cells using new intracellular fluorescent Ca indicators and ion-selective microelectrodes; contraction is recorded using video edge detectors and transducers. Cells also are permeailized or fractionated to study transport systems or receptor sites in isolation.

Selected Honors and Awards

  • Founding Fellow, International Society for Heart Research (2000)
  • Founding Fellow, American Heart Association (2000)
  • NIH/NHLBI Program Project Grant Principal Investigator (2005-2016)
  • President (elected) of International Society for Heart Research NAS (2006-2015)
  • Joseph Silva Endowed Chair for Cardiovascular Research UC Davis (2008-present)
  • NIH/NHLBI MERIT Award Recipient 2005-2015 (Nov 2008)
  • Elected Fellow of the Biophysical Society (Feb 2009)
  • Distinguished Achievement Award, American Heart Association, Basic Science Council (Nov 2009)
  • NIH Center for Scientific Review, ESTA Study Section Chair (2009-2010)
  • UC Davis School of Medicine Research Award (May 2012)
  • AHA Distinguished Scientist Award, American Heart Association (Nov 2012)

Selected Publications

Bers DM (2005) Beyond beta blockers. Nature Medicine 11:379-380.

Ziolo MT, Martin JL, Bossuyt J, Bers DM, Pogwizd SM (2005) Adenoviral gene transfer of mutant phospholamban rescues contractile dysfunction in failing rabbit myocytes with relatively preserved SERCA function. Circ Res 96: 815-817.

Bare DJ, Kettlun CS, Liang M, Bers DM, Mignery GA (2005) Cardiac type-2 inositol tris phosphate receptor: interaction and modulation by CaMKII. J Biochem 280:15912-15920.

Sanbe A, James J, Tuzcu V, Nas S, Martin L, Gulick J, Osinska H, Sakthivel S, Klevitsky R, Ginsburg KS, Bers DM, Zinman B, Lakatta EG, Robbins J (2005) Transgenic rabbit model for human troponin I-based bypertrophic cardiomyopathy. Circulation 111: 2330-2338.

Despa S, Bossuyt J, Han F, Ginsburg KS, Jia L, Kutchai HC, Tucker AL, Bers DM (2005) Phospholemman phosphorylation mediates the beta-adrenergic effects on Na/K pump function in cardiac myocytes.Circ Res 97: 252-259.

Bers DM, Guo T (2005) Calcium signaling in cardiac fentricular myocytes. Ann New York Acad Sci 1047: 86-98.

Shannon TR, Bers DM, Blatter LA, Niggli E (2005) Confocal imaging of CICR events from isolated immobilized SR vesicles. Cell Calcium 38: 497-505.

Wehrmacher WH, Puglisi JL, Bers DM, Messmore H (2005) Sudden unexpected death. Compr Ther 31: 176-180.

Bossuyt J, Ai X, Moorman RJ, Pogwizd SM, Bers DM (2005) Altered phospholemman (PLM) expression and phosphorylation in a non-ischemic, arrythmogenic rabbit heart failure model. Circ Res 97: 558-565.

Brette F, Despa S, Bers DM, Orchard CH (2005) Sarcoplasmic reticulum Ca2+ uptake and release in detubulated rat cardiac ventricular myocytes. J Molec Cell Cardiol 39: 804-812.

Shannon TR, Wang F, Bers DM (2005) Regulation of cardiac sarcoplasmic reticulum Ca release by luminal [Ca] and altered gating assessed with a mathematical modal. Biophy J 89: 4096-4110.

Ginsburg KS, Bers DM (2005) Isoproterenol does not enhance Ca-dependent Na/Ca exchange current in intact rabbit ventricular myocytes. J Molec Cell Cardiol 39: 972-981.

Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM (2005) Ca2+ - calmodulin-dependent protein kinase modulates RyR2 phosphorylation and SR Ca2+ leak in a rabbit heart failure. Circ Res 97: 1314-1322.

Ji Y, Zhao W, Li B, DeSantiago J, Picht E, Kaetzel MA, Schultz JJ, Kranias EG, Bers DM, Dedman JR (2006) Targeted inhibition of sarcoplasmic reticulum CaMKII activity results in alterations of Ca2+ homeostasis and cardiac contractibility. Am J Physiol 290: H599-H606.

Remus TP, Zima AV, Bossuyt J, Bare DJ, Martin JL, Blatter LA, Bers DM, Mignery GA (2006) Biosensors to measure InsP3 concentration in living cells with spatio-temporal resolution. J Biol Chem 281: 608-616.

Kohlhaas M, Zhang T, Seidler T, Zibrova D, Steen A, Wagner S, Chen L Heller-Brown J, Bers DM, Maier LS (2006) Acute CaMKII overexpression sensitizes SR Ca release in isolated rabbit cardiac myocytes. Circ Res 98: 235-244.

Sun J, Picht E, Bers DM, Steenbergen C, Murphy E (2006) S-nitrosylation of the L-type Ca2+ channel a1 subunit contributes to male-female differences in ischemia-reperfusion injury. Circ Res 98: 403-411.

Wu X, Zhang T, Bossuyt J, Li X, McKinsey T, Dedman JR, Olson EN, Chen J, Brown JH, Bers DM (2006) Local InsP3 -dependent perinuclear Ca signaling in cardiac myocytes excitation-transcription coupling. J Clin Invest 116: 675-682.

Bers DM, Despa S (2006) Cardiac myocytes Ca and Na regulation in normal and failing hearts. J Pharmacol Sci 100: 315-322.

Gregory KN, Ginsburg KS, Bodi I, Hahn H, Mareez YMA, Song Q, Waggoner JR, Park WJ, Schwartz A, Bers DM, Dorn GW, Karnias EG (2006) HRC: a novel regulator of sarcoplasmic reticulum calcium sequestration and cardiac function. J Molec Cell Cardiol 40: 653-665.

Bers DM (2006) Cardiac ryanodine receptor phosphorylation: target sites and functional consequences. Biocham J 396: e1-e3.

Maier LS, Ziolo MT, Bossuyt J, Persechini A, Mestril R, Bers DM (2006) Dynamic changes in free Ca-Calmodulin levels in adult cardiac myocytes. J Molec Cell Cardiol 41: 451-458.

Wu X & Bers DM (2006) Sacrcoplasmic reticulum and nuclear envelope are one highly interconnected Ca2+ store throughout cardiac myocyte. Circ Res 99: 283-291.

Guo T, Zhang T, Mestril R, Bers DM (2006) Ca/calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor does affect calcium sparks in mouse ventricular myocytes. Circ Res 99: 398-406.

Bers DM, Despa S, Bossuyt J (2006) Regulation of Ca2+ and Na+ in normal and failing cardiac myocytes. Ann New York Acad Sci 1080: 165-177.

Altamirano J, Li Y, DeSantiago J, Piacentino V, Houser SR, Bers DM (2006) The inotropic effect of cardiac glycosides in ventricular myocytes requires Na/Ca exhange function. J Physiol 575: 845-854.

Picht E, DeSantiago J, Blatter LA, Bers DM (2006) Cardiac Alternans does not rely on diastolic sarcoplasmic reticulum calcium content fluctuations. Cir Res 99: 740-748.

Bossuyt J, Despa S, Martin JL, Bers DM (2006) Phospholemman phosphorylation alters its fluoresence resonance energy transfer with the Na/K-ATPase. J Bio Chem 281: 32765-32773.

Bers DM (2006) Altered cardiac myocyte Ca regulation in heart failure. Physiology 21: 380-387.

Han F, Bossuyt J, Despa S, Tucker AL, Bers DM (2006) Phospholemman-phosphorylation mediates the PKC-dependent effects on Na/K-pump function in cardiac myocytes. Circ Res 99: 1376-1383.

Bers DM (2006) The beat goes on: Diastolic noise that just won't quit. Circ Res 99: 921-923.

Picht E, DeSantiago J, Huke S, Kaetzel MA, Dedman JR, Bers DM (2007) CaMKII inhibition targeted to the sarcoplasmic reticulum inhibits frequency dependent acceleration of relaxation and Ca2+ current facilitation. J Molec Cell Cardiol 42: 196-205.

Wu X & Bers DM (2007) Free and bound intracellular calmodulin measurements in cardiac myocytes. Cell Calcium 41: 353-364.

Berry RG, Despa S, Fuller W, Bers DM, Shattock MJ (2007) Differential distribution and regulation of mouse Na+/K+ -ATPase alpha1 and alpha2-subunits in T-tubule and surface sarcolemmal membranes. Cardiovas Res 73: 92-100.

Maier LS, Bers DM, Brown JH (2007) Calmodulin and Ca2+/calmodulin kinases in the heart-Physiology and pathophysiology. Cardiovasc Res: 73: 629-630.

Maier LS, Bers DM (2007) Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in exitation-contraction coupling in the heart. Cardiovasc Res 73: 631-640.

Islamovic E. Duncan A, Bers DM, Gerthoffer WT, Mestril R (2007) Importance of small heat shock protein 20 (HSP20) C-terminal extension in cardoiprotection. J Molec Cell Cardiol 42: 862-869.

Tocchetti CG, Wang W, Froehlich JP, Huke S, Aon MA, Wilson GM, di Denedetto G, O'Rourke B, Gao WD, Wink DA, Toscano JP, Zaccolo M, Bers DM, Valdivia HH, Cheng H, Kass DA, Paolocci N (2007) Nitroxyl improves cellular heart function by directy enhancing cardiac sarcoplasmic reticulum Ca2+ cycling. Circ Res 100: 96-104.

Huke S & Bers DM (2007) Temporal dissociation of frequency-dependent acceleration of relaxation and protein phosphorylation by CaMKII. J Molec Cell Cardiol 42: 590-599.

Curran J, Rios E, Bers DM, Shannon TR (2007) Beta-adrenergic enhancement of sarcoplasmic reticulum Ca leak in cardiac myocytes is mediated by Ca-calmodulin-dependent protein kinase. Circ Res 100: 391-398.

Yuan Q, Fan GC, Dong M, Altschafl B, Diwan A, Ren X, Hahn HH, Zhao W, Waggoner JR, Jones LR, Jones WK, Bers DM, Dorn II GW, Wang HS, Valdivia HH, Chu G, Kranias EG (2007) Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility, but increases ventricular automacticity. Circulation 115: 300-309.

Bers DM & Ginsburg KS (2007) Na:Ca stoichometry and cytosolic Ca-dependent activation of NCX in intact cardiomyocytes. Ann New York Acad Sci 1099:326-338.

Higgins E, Goel P, Puglisi JL, Bers DM, Cannell M, Sneyd J (2007) Modeling calcium microdomains using homogenisation. J Theoret Biol 247: 623-644.

Picht E, Zima AV, Blatter LA, Bers DM (2007) SparkMaster - Automated calcium spart analysis with image. Am J Physiol Cell Physiol 293: C1073-1081.

Altamirano J, Bers DM (2007) Effects of intracellular Ca and action potential duration on L-type Ca current inactivation and recovery in cardiac myocytes. Am J Physiol Heart Circ Physiol 293:H563-573.

Despa S, Bers DM (2007) Functional analysis of Na+/K+ -ATPase isoform distribution in rat ventricular myocytes.  Am J Physiol. Cell Physiol. 293: C321-C327.

Altamirano J, Bers DM (2007) Voltage-dependence of cardiac excitation-contraction coupling: Unitary current amplitude and open channel probability. Circ Res 101(6):590-597.

Bers DM (2007) Going to cAMP just got more complicated. J Physiol. 583 (pt.2): 415-416.

Grandi E, Puglisi JL, Wagner S, Maier LS, Severi S, Bers DM (2007) Simulation of Ca/Calmodulin-dependent protein kinase II on rabbit ventricular myocyte ion currents and action potentials. Biophys J 93: 3835-3847.

Guo T, Ai X, Shannon TR, Pogwizd SM, Bers DM (2007) Intra-sarcoplasmic reticulum free [Ca] and buffering in arrhythmogenic failing rabbit heart. Circ Res 101(8): 802-810.

Zhang T, Kohlhaas M, Backs J, Mishra S, Phillips W, Dybkova N, Chang S, Ling H, Bers DM, Maier LS, Olson EN, Brown JH (2007) CaMKIIdelta isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses. J Biol Chem

Puglisi LJ, Wehrmacher WH, Messmore H, Bers DM (2007) Pulmonary arterial hypertension. Compr Ther 33: 231-236.

Bers DM (2008) Calcium cycling and signaling cardiac myocytes. Annual Rev Physiol 70: 17.1 - 17.27.

 

See: Complete List of Publications