Forchheimer Building G42
Professor, Department of Medicine (Cardiology)
Professor, Department of Molecular Pharmacology
Regulation of Cardiac Ion Channel Function: The Na+ channel (SCN5A, LQT3) and two K+ channels, HERG (LQT2) and KVLQT1 (LQT1) are linked to the inherited Long QT Syndrome and are responsible for cardiac action potential initiation and termination for each heart beat. Appropriate activation of these channels terminates each action potential allowing the next heart beat to occur in a normal fashion. Macromolecular signaling complexes involving channels may serve multiple functions including assembly, trafficking, targeting, and recycling of the channel proteins. Dynamic, beat-to-beat regulation of cardiac ion channels is likely to be precisely controlled given that both acquired and inherited ventricular arrhythmias are usually episodic and precipitated by some stimulus or stress. Moreover, such regulation may underlie the responses to cardiovascular challenges and stresses that eventually lead to maladaptive "electrical remodeling" with cardiac arrhythmias.
The McDonald laboratory employs a multifaceted approach to understand how these channels are regulated by accessory subunits, protein kinases, and adaptor proteins. Specific projects focus on:
- Dynamics of ion channel protein translation in acquired and hereditary cardiac disorders.
- Epigenetic factors regulating K+ channel expression.
- Second-messenger regulation of channel function by electrophysiological measurements of cloned channels in a heterologous expression system.
- The main focus is on channel effects of acute and chronic adrenergic stimulation as adaptive and/or maladaptive stimuli for propensity towards arrhythmia.
- Functional and physical analysis of potassium channel interactions with accessory proteins through electrophysiological and biochemical/structural analyses.
- Regulation of channel protein translation is being studied with respect to kinase mediated effects and contributions of mRNA secondary structure towards protein folding and trafficking.
- Discovery and functional analysis of novel mutations and genetic loci for inherited cardiac arrhythmias (LQTS, Brugada Syndrome, CPVT, SIDS) from families evaluated in the Montefiore-Einstein Center for CardioGenetics.
Potassium Channels of Protozoan Parasites: All living cells express membrane ion channels that are evolutionarily conserved. These channels provide selective permeability characteristics of cell membranes and are essential for normal cell function and viability. The McDonald laboratory has identified and cloned a series of related K+ channel genes from intracellular parasite genomes (Malaria, Leishmania, Toxoplasma) and mycobacterium. They are now investigating these channel gene products for their roles as determinants of cell function, viability, infectivity and virulence. The long term goal of this research is to identify essential functional proteins that may serve as pharmacological or immunological targets.
- Chen J, Chen K, Sroubek J, Wu Z-Y, Bian J-S, McDonald TV. Post-transcriptional control of HERG potassium channel protein by -adrenergic receptor stimulation. Molecular Pharmacology Aug;78(2):186-97. 2010, PMID: 20463060.
- Sroubek J & McDonald TV. Protein Kinase A Activity at the Endoplasmic Reticulum Surface Is Responsible for Augmentation of Human ether-a-go-go-related Gene Product (HERG). J Biol Chem. 286:21927-21936. 2011. PMID: 21536683.
- Krishnan Y, Li Y, Zheng R, Kanda V, McDonald TV. Mechanisms underlying the protein-kinase mediated regulation of the HERG potassium channel synthesis. Biochimica et Biophysica Acta - Molecular Cell Research 1823:1273-1284. 2012. PMID: 22613764
- Erskine K, Griffith E, DeGroat N, Stolerman M, Silverstein LB, Hidayatalla N, Wasserman D, Paljevic E, Cohen L, Walsh CA, McDonald T, Marion RW, Dolan SM. An Interdisciplinary Approach to Personalized Medicine: Case Studies from a Cardiogenetics Clinic. Personalized Medicine 10:73-80. 2013. PMID: 24496296
- Sroubek J, Krishnan Y, McDonald TV. Sequence and structure-specific elements of HERG mRNA regulate channel synthesis and trafficking. FASEB J (Epub) 2013 April 22. PMID: 23608144
McDonald Lab Page
Molecular Pharmacology Page