Howard C. Kutchai

Education

  • PhD, University of Virginia

Primary Appointment

  • Professor, Molecular Physiology and Biological Physics

Contact

Research Interest(s)

Quaternary Structure of Calcium-ATPases of sarcoplasmic reticulum and Na, K-ATPase and Its Regulatory Significance

Research Description

SERCA2a [the Ca-ATPase of sarcoplasmic reticulum (SR) of cardiac muscle] plays a central role in intracellular calcium dynamics and thus in the contractility of the heart. The SR regulates the movement of calcium during both contraction and relaxation of the heart.  The action potential leads to the opening of voltage-gated L-type calcium channels in the plasma membrane, allowing the entry of a small amount of calcium, which then triggers the release of a much larger amount of calcium from the SR and subsequent contraction.  During relaxation, calcium is pumped back into the SR by SERCA2a and extruded to the extracellular fluid by the plasma membrane Na+/Ca2+ exchanger. If more Ca2+ is taken up into SR during diastole, more can be released in the next systole, so that the force and speed of contraction are expected to increase.  Stimulation of SERCA2a should also increase the rate of decrease of ventricular pressure in diastole.  A good deal of previous research supports the interpretation that decreased activity of SERCA2a may be involved in heart failure and that interventions that increase the activity of SERCA2a have beneficial effects in heart failure.  Decreased SERCA2a activity has been implicated in the abnormal Ca2+ homeostasis in animal models of heart failure and in failing human hearts.  Mice whose levels of SERCA2a has been increased by gene transfer are protected against some of the consequences of experimental heart attack.

We are studying the effects of novel synthetic compounds that significantly increase the activity of SERCA2a.  We will characterize the effects of these compounds on contractility in hearts of normal mice and in mice subjected to experimental myocardial infarction and determine whether the compounds can ameliorate the rhythm disturbances that occur following heart attack.

Selected Publications

  • Mahaney J, Albers R, Waggoner J, Kutchai H, Froehlich J. Intermolecular conformational coupling and free energy exchange enhance the catalytic efficiency of cardiac muscle SERCA2a following the relief of phospholamban inhibition. Biochemistry. 2005;44(21): 7713-24. PMID: 15909986
  • Rembold C, Ripley M, Meeks M, Geddis L, Kutchai H, Marassi F, Cheung J, Moorman J. Serine 68 phospholemman phosphorylation during forskolin-induced swine carotid artery relaxation. Journal of vascular research. 2005;42(6): 483-91. PMID: 16155364 | PMCID: PMC1266286
  • Reddy S, Mistry D, Wang Q, Geddis L, Kutchai H, Moorman J, Mounsey J. Effects of age and gene dose on skeletal muscle sodium channel gating in mice deficient in myotonic dystrophy protein kinase. Muscle & nerve. 2002;25(6): 850-7. PMID: 12115974