Ph.D, Australian National UniversityPhone: (631) 444-7334
Fax: (631) 632-6661
Basic Sciences Tower 6
David McKinnon received a B.Sc. in Physiology from the University of New South Wales, Australia, in 1983 and a Ph.D. in Physiology from the John Curtin School of Medical Research, Australian National University in 1987. Between 1987 and 1990, he was a Post-Doctoral Fellow at the Salk Institute and then at Washington University. In 1991 he joined the State University of New York at Stony Brook as Assistant Professor of Neurobiology and Behavior and was promoted to full professor in 2005.
Our lab is interested in two questions:
- How do cellular electrophysiological systems evolve.
- To what extent does homeostatic regulation control ion channel expression in the adult.
Evolution of Cellular Electrophysiological Systems
Remarkably little is known about the evolution of complex physiological systems, as opposed to the evolution of individual physiologically important proteins. Cellular electrophysiological systems are ideal systems in which to study this issue because they can be described in a quantitative fashion using mathematical models. In addition, the properties of voltage-gated ion channels, which determine the cellular electrophysiological phenotype, can be accurately measured using electrophysiological recording techniques.
We currently study two specific issues:
- What is the relative importance of structural evolution, the modification of ion channel structure and function, compared to the role of regulatory evolution, the evolution of ion channel gene expression, for the evolution of cellular electrophysiological systems.
- What are the constraints that limit the possible pathways for evolutionary change in these systems.
Homeostatic Regulation of Ion Channel Expression
Regulation of ion channel expression is critical for the maintenance of the function of electrically excitable cells. Surprisingly, human genetic studies have shown that for many ion channel genes the loss of one allele results in severe, often life threatening, consequences. These results suggest that there is very little feedback regulating channel expression from the remaining allele or from other genes that could compensate for the loss. In principle, there are a large number of points at which homeostatic regulation could act to control ion channel expression (see Figure), but in practice very few homeostatic regulatory mechanisms appear to function in the adult.
Understanding what homeostatic mechanisms are, and are not, available to regulate the function of these systems is the focus of our study. We use conditional knockout mice in which we can selectively eliminate, one or both alleles of a given ion channel gene in the adult mouse in order to study the consequences of that loss on the molecular and cellular physiology of the animal.
- Laboratory Personnel
- Yan Q., Masson R., Ren Y., Rosati B., McKinnon D. (2012) Evolution of CpG island promoter function underlies changes in KChIP2 potassium channel subunit gene expression in mammalian heart. Proc. Natl. Acad. Sci., 109, 1601-1606.
- Rosati, B., Yan, Q., Lee, M.S, Liou, S-R., Ingalls, B., Foell, J., Kamp, T.J. and McKinnon, D. (2011) Robust L-Type Calcium Current Expression following Heterozygous Knockout of the Cav1.2 Gene in Adult Mouse Heart. J. Physiol., 589, 3275–3288. [link]
- Rosati, B. and McKinnon, D. (2009) Structural and regulatory evolution of cellular electrophysiological systems. Evol Dev, 11, 610-618. [pdf]
- Rosati, B., Dong, M., Cheng, L., Liou, S.-R., Yan, Q., Park, J.Y., Shiang, E., Sanguinetti, M., Wang, H.-S. and McKinnon, D. (2008) Evolution of ventricular myocyte electrophysiology. Physiol Genomics, 35, 262-272. [pdf]
- Rosati, B. and McKinnon, D. (2004) Control of Ion Channel Expression. Circ. Res., 94, 874-883.
- Rosati, B., Grau, F., Rodriguez, S., Li, H., Nerbonne J. M. and McKinnon, D. (2003) Concordant Expression of KChIP2 mRNA, Protein and Transient Outward Current throughout the Canine Ventricle. J. Physiol., 548, 815-822.
- Wang, H.-S., Pan, Z., Shi, W., Brown, B. S., Wymore, R.S., Cohen, I. S., Dixon, J. E. and McKinnon, D. (1998) KCNQ2 and KCNQ3Potassium Channel Subunits: Molecular Correlates of the M-Channel. Science, 282, 1890-1893.
- Dixon, J. E., Shi, W., Wang, H.-S., MacDonald, C., Yu, H., Wymore, R. S., Cohen, I. S. and McKinnon, D. (1996). Role of the Kv4.3 K+ channel in ventricular muscle: a molecular correlate for the transient outward current. Circ. Res., 79, 659-668.
- Wang, H.-S. and McKinnon, D. (1995). Potassium currents in prevertebral and paravertebral sympathetic neurones: Control of firing properties. J. Physiol., 485, 319-335.
- McKinnon, D. (1989) Isolation of a cDNA clone coding for a putative second potassium channel indicates the existence of a gene family. J. Biol. Chem., 264, 8230-8236.
- McKinnon, D. and Ceredig, R. (1986) Changes in the expression of potassium channels during mouse T cell development. J. Exp. Med., 164, 1846-1861.
- Barbara Rosati - Research Assistant Professor
- Shian-Ren Liou – Postdoctoral Associate