Research in the Anderson laboratory focuses on cellular signaling and ionic mechanisms that cause heart failure, arrhythmias and sudden cardiac death, major public health problems worldwide. Our primary focus is on the multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII). Our laboratory identified CaMKII as an important pro-arrhythmic and pro-cardiomyopathic signal. These studies have provided proof of concept evidence motivating active efforts in biotech and the pharmaceutical industry to develop therapeutic CaMKII inhibitory drugs to treat heart failure and arrhythmias.
CaMKII is activated by increased intracellular Ca2+ and oxidation. Diverse ‘upstream’ signals, including catecholamines and the renin-angiotensin-aldosterone pathway increase CaMKII activity. CaMKII is multifunctional because it has multiple ‘downstream’ targets. CaMKII catalyzed phosphorylation in myocardium appears to coordinate activity of many or most voltage-gated ion channels, Ca2+ homeostatic proteins and gene transcription events.
Under physiological conditions, CaMKII is important for excitation-contraction coupling and fight or flight increases in heart rate. However, myocardial CaMKII is excessively activated during disease conditions where it contributes to loss of intracellular Ca2+ homeostasis, membrane hyperexcitability, premature cell death, and hypertrophic and inflammatory transcription. These downstream targets appear to contribute coordinately and decisively to heart failure and arrhythmias. Recently, we have developed evidence that CaMKII also participates in asthma.
Wu Y, Valdivia HH, Wehrens XH, Anderson ME. A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol. 2016 Feb;9(2):e003180. doi: 10.1161/CIRCEP.115.003180. PMID: 26857906.
Rasmussen TP, Wu Y, Joiner ML, Koval OM, Wilson NR, Luczak ED, Wang Q, Chen B, Gao Z, Zhu Z, Wagner BA, Soto J, McCormick ML, Kutschke W, Weiss RM, Yu L, Boudreau RL, Abel ED, Zhan F, Spitz DR, Buettner GR, Song LS, Zingman LV, Anderson ME. Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):9129-34. doi: 10.1073/pnas.1504705112. Epub 2015 Jul 7. PMID: 26153425
Wu Y, Rasmussen TP, Koval OM, Joiner ML, Hall DD, Chen B, Luczak ED, Wang Q, Rokita AG, Wehrens XH, Song LS, Anderson ME. The mitochondrial uniporter controls fight or flight heart rate increases. Nat Commun. 2015 Jan 20;6:6081. doi: 10.1038/ncomms7081. Erratum in: Nat Commun. 2015;6:7241. PMID: 25603276
Lai MH, Wu Y, Gao Z, Anderson ME, Dalziel JE, Meredith AL. BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo. Am J Physiol Heart Circ Physiol. 2014 Nov 1;307(9):H1327-38. doi: 0.1152/ajpheart.00354.2014. Epub 2014 Aug 29. PubMed PMID: 25172903; PubMed Central PMCID: PMC4217012.
Hall DD, Wu Y, Domann FE, Spitz DR, Anderson ME. Mitochondrial Calcium Uniporter Activity Is Dispensable for MDA-MB-231 Breast Carcinoma Cell Survival. PLoS One. 2014 May 6; 9(5):e96866. doi: 10.1371/journal.pone.0096866.