F A C U L T Y P R O F I L E
ROBINSON, RICHARD B., PH.D.
Regulation of cardiac ion channels and autonomic signaling by development and disease; gene and cell therapies for cardiac arrhythmias.
Office: Prebyterian Hospital | 7W 318
My laboratory is concerned with elucidating the processes that control developmental regulation of cardiac ion channel expression (i.e. electrical behavior) and cardiac autonomic responsiveness (i.e. sensitivity to neurotransmitters), and using that knowledge to design gene- and cell-based therapies for cardiac disease.
We study heart cells grown alone in culture, or co-cultured with neurons or mesenchymal stem cells. We employ a range of techniques, including standard electrophysiology, whole cell voltage clamp and fluorescence microscopy with ion sensitive dyes. By studying both native cardiac channels and recombinant channels over-expressed in myocytes we explore the molecular mechanisms that control channel function within the heart cell and the impact of development and disease on these mechanisms. We also take advantage of transgenic animals in which selected signaling elements have been disrupted or altered.
We have identified age-dependent differences in the function and expression of several cardiac ionic channels (including INa, ICa,L and If), and also differences in autonomic signal transduction cascades (including alpha- and beta-adrenergic and cholinergic) that modulate these and other ionic channels in the heart. We have further found that neurons exert a trophic influence to modify heart cell development that can account for some of the age-dependent effects on ion channel function and the cardiac cell's response to autonomic agonists. Both neurally released peptides (e.g. NPY) and more familiar neurotransmitters (e.g. norepinephrine) can serve as developmental factors.
Our increasing understanding of the factors that regulate channel function within the heart cell allows us to develop genetic therapies in which selected channels are over-expressed in the in situ heart, either within the myocytes or in stem cells that then couple to the myocytes, for the purpose of regulating cardiac rhythm. Recent efforts in this regard have resulted in proof-of-concept studies creating a biological pacemaker to augment or replace current electronic pacemakers and enhancing conduction to disrupt reentrant arrhythmias associated with myocardial infarction.
1. Kryukova Y, Rybin VO, Qu J, Steinberg SF, Robinson RB: Age-dependent inhibition of HCN2 current in rat ventricular myocytes by the tyrosine kinase inhibitor erbstatin. Pflugers Archiv 457:821-830, 2009.
2. Protas L, Dun W, Jia Z, Lu J, Bucchi A, Kumari S, Chen M, Cohen IS, Rosen MR, Entcheva E, Robinson RB: Expression of Skeletal but not Cardiac Na Channel Isoform Preserves Normal Conduction in a Depolarized Cardiac Syncytium. Cardiovasc Res 81:528-535, 2009.
3. Zhao X, Bucchi A, Oren RV, Kryukova Y, Dun W, Clancy CE, Robinson RB: In vitro characterization of HCN channel kinetics and frequency-dependence in myocytes predicts biological pacemaker functionality. J Physiol 587:1513-1525, 2009.
4. Protas L, Oren RV, Clancy CE, Robinson RB: Age-dependent changes in Na current magnitude and TTX-sensitivity in the canine sinoatrial node. J Mol Cell Cardiol 48:172-180, 2010.
5. Shlapakova IN, Nearing BD, Lau DH, Boink GJJ, Danilo P Jr, Kryukova Y, Robinson RB, Cohen IS, Rosen MR, Verrier RL: Biological Pacemakers in Canines Exhibit Positive Chronotropic Response to Emotional Arousal. Heart Rhythm 12:1835-1840, 2010