Emeritus Professor Angela Dulhunty AM
Contacts
Dulhunty graduated from The University of Sydney, Australia, in 1969 with a Bachelor of Science degree and Honours in Physiology. She obtained a PhD from the University of NSW in 1973 presenting a thesis describing muscle electrophysiology studies carried out with Professor Peter Gage. She was then awarded a Muscular Dystrophy Postdoctoral Fellowship to work at the University of Rochester (NY) with Professors Paul Horowicz, Clara Franzini-Armstrong and Camillo Peracchia. She returned to Australia in 1975 and established a Muscle Research Laboratory in the Department of Anatomy at The University of Sydney. In 1982 Dulhunty, with Professors Peter Gage and Peter Parry, was awarded and a Centre of Excellence for Nerve Muscle Research at the University of NSW. The Centre moved to the Australian National University in Canberra in 1984, where Dulhunty re-established the Muscle Research Laboratory. She was awarded a DSc degree by the University of NSW in 1988 for her extensive research into muscle excitation-contraction coupling (ECC). Dulhunty was appointed to an Emeritus position at the ANU in 2017. In 2022, she was awarded an AM (Australian Medal) for contributions to Medical Research and Student training
Dulhunty's research has focussed on the translation of electrical signals in the surface membrane of muscle fibres into the release of the calcium ions from their internal in the sarcoplasmic reticulum (SR), to enable muscle contraction in the process of excitation contraction coupling (ECC). In her PhD studies she explored the complex nature of transverse (T-) tubule extensions of the surface membrane which conduct the surface electrical signal throughout the fibre cross-section. The discovery of asymmetric charge movement arising from dihydropyridine receptors in T-tubules allowed her to examine this voltage sensor for ECC in fast and slow-twitch mammalian muscle and to apply this to her subsequent studies of the voltage dependence for ECC. The other major component of ECC, the ryanodine receptor (RyR) calcium release channel in the SR, was identified in the late 1980s. Dulhunty was amongst the first researchers to study single RyR ion channels from skeletal and cardiac muscle using lipid bilayer electrophysiology. She has continued to study RyR channels, combining electrophysiology, biochemistry, protein chemistry, structural biology and molecular biology to explore normal RyR function and pathological changes that reduce skeletal muscle function and which can compromise cardiac muscle to the extent of causing heart attack.
Research interests
The interests in the Muscle Research Group include the molecular structure and function of the proteins that regulate Ca2+ signalling and contraction in skeletal muscle and the heart. These include two ion channel proteins, the dihydropyridine receptor (DHPR) Ca2+ channel in the surface membrane and the ryanodine receptor (RyR) Ca2+ release channel in the sarcoplasmic reticulum (SR) Ca2+ store. The two proteins are essential for muscle function, movement and heart beat. Excitation-contraction (EC) coupling is broadly defined as the signal transduction process that links a surface membrane action potential to contraction. More narrowly the term encapsulates the processes that intervene between the action potential depolarization and Ca2+ release from the SR. EC coupling in the heart depends on RyR activation by Ca2+ ions that enter the muscle cell through the DHPR ion channel. In marked contrast, EC coupling in skeletal muscle does not depend on external Ca2+. Instead, a depolarisation-dependent signal is transmitted from the DHPR to the RyR by a cascade of conformational change through several other essetial proteins that link the DHPR with the RyR. The nature of this protein complex and the proteins within it remain an area of intense investigation and a focus of the muscle Research group. Our goal is to understand the normal function of the proteins that regulate Ca2+ signalling and changes in the function of the proteins that lead to skeletal myopathies and in heart disease.
Although many of our questions are very basic, the research is increasingly directed to understanding disease-related mutations in the proteins that are linked to debilitating skeletal myopathies and to fatal cardiomyopathies. The long-term goal in this regard is the rational design of drugs that might help alleviate the symptoms of these disorders.
Groups
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Publications for last 10 years:
Dulhunty, A, 2023, ‘Biophysical reviews top five: voltage‑dependent charge movement in nerve and muscle. Biophysical Reviews.
Salvage S, Dulhunty A, Jeevaratnam K, Jackson A, Huang C, 2023, ‘ Feedback contributions to excitation-contraction coupling in native functioning striated muscle’ Philosophical Transactions of the Royal Society of London Series B, vol. 378 no 1879, 20220162
Richardson, S, Thekkedam, C, Casarotto, M et al. 2023, 'FKBP12 binds to the cardiac ryanodine receptor with negative cooperativity: implications for heart muscle physiology in health and disease', Philosophical Transactions of the Royal Society of London Series B, vol. 378, no. 1879 20220169.
Maxwell M, Thekkedam C, Lamboley C et al. 2023, ‘A bivalent remipede toxin promotes calcium release via ryanodine receptor activation’, Nature Communications, vol. 14(1):1036.
Shishmarev, D, Rowland, E, Aditya, S et al. 2022, 'Molecular interactions of STAC proteins with skeletal muscle dihydropyridine receptor and excitation-contraction coupling', Protein Science, vol. 31, no. 5, pp. 1-11.
Dulhunty, A 2022, 'Molecular Changes in the Cardiac RyR2, With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)', Frontiers in Physiology, vol. 13, pp. 1-7.
Salvage, S, Huang, C, Fraser, J et al. 2022, 'How does flecainide impact RyR2 channel function?' Journal of General Physiology, vol. 154, no. 9, pp. 1-23.
Salvage, S, Gallant, P, Fraser, J et al. 2021, 'Flecainide Paradoxically Activates Cardiac Ryanodine Receptor Channels under Low Activity Conditions: A Potential Pro-Arrhythmic Action', Cells, vol. 10, no. 8.
Robinson, K, Culley, D, Waring, S et al. 2020, 'Peptide mimetic compounds can activate or inhibit cardiac and skeletal ryanodine receptors', Life Sciences, vol. 260, pp. 1-16.
O'Meara, C, Coupland, L, Kordbacheh, F et al. 2020, 'Neutralizing the pathological effects of extracellular histones with small polyanions', Nature Communications, vol. 11, no. 1.
Salvage, S, Gallant, P, Beard, N et al. 2019, 'Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse', Journal of Cell Science, vol. 132, no. 10.
Chakraborty, A, Gonano, L, Munro, M et al. 2019, 'Activation of RyR2 by class I kinase inhibitors', British Journal of Pharmacology, vol. 176, no. 6, pp. 773-786.
Perez, C, Eltit, J, Lopez, J et al 2018, 'Functional and structural characterization of a novel malignant hyperthermia-susceptible variant of DHPR-β1a subunit (CACNB1)', American Journal of Physiology - Cell Physiology, vol. 314, no. 3, pp. 323-333pp.
Denniss, A, Dulhunty, A & Beard, N 2018, 'Ryanodine receptor Ca2+ release channel post-translational modification: Central player in cardiac and skeletal muscle disease', The International Journal of Biochemistry and Cell Biology, vol. 101, pp. 49-53.
Robinson, K, Easton, C, Dulhunty, A et al. 2018, 'Exploiting Peptidomimetics to Synthesize Compounds That Activate Ryanodine Receptor Calcium Release Channels', ChemMedChem, vol. 13, no. 18, pp. 1957-1971
Dulhunty, A, Beard, N & Casarotto, M 2018, 'Recent advances in understanding the ryanodine receptor calcium release channels and their role in calcium signalling [version 1; peer review: 4 approved]', F1000 Research, vol. 7.
Walweel, K, Molenaar, P, Imtiaz, M et al 2017, 'Ryanodine receptor modification and regulation by intracellular Ca2+ and Mg2+ in healthy and failing human hearts', Journal of Molecular and Cellular Cardiology, vol. 104, no. March 2017, pp. 53-62.
Dulhunty, A, Wei-LaPierre, L, Casarotto, M et al 2017, 'Core skeletal muscle ryanodine receptor calcium release complex', Clinical and Experimental Pharmacology and Physiology, vol. 44, no. 1, pp. 3-12.
Dulhunty, A, Board, P, Beard, N et al 2017, 'Physiology and Pharmacology of Ryanodine Receptor Calcium Release Channels', Advances in Pharmacology, vol. 79, pp. 287-324.
Norris, N, Joseph, S, Aditya, S et al. 2017, 'Structural and biophysical analyses of the skeletal dihydropyridine receptor β subunit β1a reveal critical roles of domain interactions for stability', Journal of Biological Chemistry, vol. 292, no. 20, pp. 8401-8411.
Salvage, S, Chandrasekharan, K, Jeevaratnam, K et al 2017, 'Multiple targets for flecainide action: Implications for cardiac arrhythmogenesis', British Journal of Pharmacology, vol. 175, no. 8, pp. 1260-1278.
Hanna, A, Lam, A, Thekkedam, C et al. 2017, 'The anthracycline metabolite doxorubicinol abolishes RyR2 sensitivity to physiological changes in luminal Ca21 through an interaction with calsequestrin', Molecular Pharmacology, vol. 92, no. 5, pp. 576-587.
Richardson, S, Steele, G, Gallant, P et al. 2017, 'Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding', Journal of Cell Science, vol. 130, no. 20, pp. 3588-3600.
van Zyl, H, Theodoratos, A, Smith, P et al. 2016, 'Unexpected dependence of RyR1 splice variant expression in human lower limb muscles on fiber-type composition', Pflugers Archives European Journal of Physiology, vol. 468, no. 2, pp. 269-278.
Hewawasam, R, Liu, D, Casarotto, M et al. 2016, 'The GSTM2 C-Terminal domain depresses contractility and Ca2+ transients in neonatal rat ventricular cardiomyocytes', PLOS ONE (Public Library of Science), vol. 11, no. 9, pp. e0162415-e0162415.
Wium, E, Dulhunty, A & Beard, N 2016, 'Three residues in the luminal domain of triadin impact on Trisk 95 activation of skeletal muscle ryanodine receptors', Pflugers Archives European Journal of Physiology, vol. 468, no. 11-12, pp. 1985-1994.
Rebbeck, R, van Zyl, H, Groom, L et al. 2015, 'Regions of ryanodine receptors that influence activation by the dihydropyridine receptor β1a subunit', Skeletal Muscle, vol. 5, no. 23, pp. 1-15.
Li, L, Mirza, S, Richardson, S et al. 2015, 'A new cytoplasmic interaction between junctin and ryanodine receptor Ca2+ release channels', Journal of Cell Science, vol. 128, no. 5, pp. 951-963.
Beard, N & Dulhunty, A 2015, 'C-terminal residues of skeletal muscle calsequestrin are essential for calcium binding and for skeletal ryanodine receptor inhibition', Skeletal Muscle, vol. 5, no. 1, pp. 1-12pp.
Rebbeck, R, van Zyl, H, Groom, L et al. 2015, 'Regions of ryanodine receptors that influence activation by the dihydropyridine receptor β1a subunit', Skeletal Muscle, vol. 5, no. 23, pp. 1-15.
Samarasinghe, S, Liu, D, Tummala, D et al. 2015, 'Glutathione transferase M2 variants inhibit ryanodine receptor function in adult mouse cardiomyocytes', Biochemical Pharmacology, vol. 97, no. 3, pp. 269-280.
Walweel, K, Li, J, Molenaar, P et al 2014, 'Differences in the regulation of RyR2 from human, sheep, and rat by Ca2+ and Mg2+ in the cytoplasm and in the lumen of the sarcoplasmic reticulum', Journal of General Physiology, vol. 144, no. 3, pp. 263-271.
Rebbeck, R, Karunasekara, Y, Board, P et al. 2014, 'Skeletal muscle excitation-contraction coupling: Who are the dancing partners?', The International Journal of Biochemistry and Cell Biology, vol. 48, no. 1, pp. 28-38.
Hernandez-Ochoa, E, Olojo, R, Rebbeck, R et al 2014, β1a490-508, a 19-residue peptide from C-terminal tail of Cav1.1 α1a subunit, potentiates voltage-dependent calcium release in adult skeletal muscle fibers', Biophysical Journal, vol. 106, no. 3, pp. 535-547.
Hanna, A, Lam, A, Thekkedam, C et al. 2014, 'Cardiac ryanodine receptor activation by a high Ca2+ store load is reversed in a reducing cytoplasmic redox environment', Journal of Cell Science, vol. 127, no. 20, pp. 4531-4541.
Hanna, A, Lam, A, Tham, S et al. 2014, 'Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A', Molecular Pharmacology, vol. 86, no. 4, pp. 438-449.
Li, J, Imtiaz, M, Beard, N et al. 2013, ' β-Adrenergic Stimulation Increases RyR2 Activity via Intracellular Ca2+ and Mg2+ Regulation', PLOS ONE (Public Library of Science), vol. 8, no. 3, pp. e58334-e58334.
Smith, J, Vetter, I, Lewis, R et al. 2013, 'Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins', PNAS - Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 22, pp. 8906-8911.
