Howard Kutchai, Ph.D.
|Address:||Molecular Physiology and Biological Physics
University of Virginia
PO Box 800736
Charlottesville, VA 22908-0736
The subject of our research is the calcium ATPase of sarcoplasmic reticulum of skeletal and cardiac muscle. We are investigating the hypothesis that the oligomeric state of the calcium ATPase in the sarcoplasmic reticulum membrane is of regulatory significance. The time dependence of the anisotropy of a covalent phosphorescent label on the calcium ATPase is used to estimate the mole fractions of monomeric, dimeric, tetrameric, and higher order oligomers of the calcium ATPase. Calcium, the inhibitors thapsigargin and cyclopiazonic acid, and local and general anesthetics have been found to modulate both the activity and the oligomeric state of the calcium ATPase. Thus far our results suggest that monomers and dimers of the calcium ATPase have full activity, but tetramers and larger aggregates have much less activity.
More recently we have been studying the effects of local and general anesthetics on the activity and oligomeric state of the Na,K-ATPase of canine kidney. Local anesthetics strongly inhibit the activity of the Na,K-ATPase at anesthetic concentrations within the range at which they are used clinically. We will investigate whether inhibition of Na,K-ATPase contributes to the mechanism of action of local anesthetics.
Kutchai, H., Mahaney, J.E., Geddis, L.M. and Thomas, D.D. (1994) Hexanol and lidocaine affect the oligomeric state of the Ca-ATPase of sarcoplasmic reticulum. Biochemistry 33:13208-13222. [View Entrez Listing]
Karon, B.S., Geddis, L.M., Kutchai, H. and Thomas, D.D. (1995) Anesthetics alter the physical and functional properties of the Ca-ATPase in cardiac sarcoplasmic reticulum. Biophys. J. 68:936-945, 1995. [View Entrez Listing]
Mersol, J.V., Kutchai, H., Mahaney, J.E. and Thomas, D.D. (1995) Self-association accompanies inhibition of Ca-ATPase by thapsigargin. Biophys. J. 68:208-215. [View Entrez Listing]
Shi, Y., Karon, B.S., Kutchai, H., and Thomas, D.D. (1996) Phospholamban-dependent effects of C12E8 on calcium transport and molecular dynamics in cardiac sarcoplasmic reticulum. Biochemistry 35:13393-13399. [View Entrez Listing]
Kutchai H, Geddis LM, Jones LR, Thomas DD. Differential effects of general anesthetics on the quaternary structure of the Ca-ATPases of cardiac and skeletal sarcoplasmic reticulum. Biochemistry. 1998 Feb 24;37(8):2410-21.PMID: 9485389 [View Entrez Listing]
Kutchai H, Geddis LM, Farley RA. Effects of general anaesthetics on the activity of the Na,K-ATPase of canine renal medulla. Pharmacol Res. 1999 Dec;40(6):469-73.PMID: 10660943 [View Entrez Listing]
Kutchai H, Geddis LM, Farley RA. Effects of local anaesthetics on the activity of the Na,K-ATPase of canine renal medulla. Pharmacol Res. 2000 Jan;41(1):1-7.PMID: 10600263 [View Entrez Listing]
Kutchai H, Geddis LM. Inhibition of the Na,K-ATPase of canine renal medulla by several local anesthetics. Pharmacol Res. 2001 Apr;43(4):399-403.PMID: 11352545 [View Entrez Listing]
Rembold CM, Ripley ML, Meeks MK, Geddis LM, Kutchai HC, Marassi FM, Cheung JY, Moorman JR. Serine 68 phospholemman phosphorylation during forskolin-induced swine carotid artery relaxation.J Vasc Res. 2005 Nov-Dec;42(6):483-91. Epub 2005 Sep 6.PMID: 16155364 [View Entrez Listing]