Physiology and Biophysics Faculty

Research Interests

Research interests are in two general areas: Ion channels and transmitter release.

Ion channels are large protein macromolecules that span cell membranes. They open and close, or gate their pores, controlling the flux of ions across cell membranes. Since the flux of ions determines the membrane potentials of cells, ion channels play a key role in controlling the electrical activity of nerve and muscle cells. My laboratory studies ion channels. We are specifically interested in characterizing the types of ion channels in different cells, and determining the mechanisms by which the different channels open and close their pores (gating) and select for the passage of specific ions (selectivity) Gating and selectivity are studied by recording currents flowing through single ion channels with the patch clamp technique. Opening and closing of a single channel can be indirectly observed through step changes in the current through the channels, and the ability of a channel to carry current can be determined directly from the magnitude of the single-channel current.

Detailed studies of the opening and closing durations using extensive computer analysis and numerical methods allows kinetic gating mechanism to be determined. Analysis of the effect of different ions on the magnitude of current flowing through open channels gives insight into the mechanism by which a channel selects for some ions and excludes others. Channels currently under investigation in my laboratory are a large conductance calcium-activated potassium channel (BK channel) and several different chloride channels. For the BK channel, both wild type and cloned channels with various structural modifications are studied to give insight into the relationship between structure and gating mechanism.

Synapses are the main site of information transfer among neurons and from neurons to output organs such as muscle. During and following repetitive stimulation the amount of transmitter released at synapses varies depending on the frequency and duration of stimulation. My laboratory studies the mechanisms underlying the short-term changes in transmitter release (short-term synaptic plasticity). Calcium imaging techniques are used to measure free intracellular calcium which is then related to the changes in transmitter release through kinetic models to test models for the underlying mechanism of short-term synaptic plasticity.  

The above figure presents a schematic diagram of a proposed gating mechanism for BK channels. Ca2+ binds to the gating ring comprised of eight RCK domains (A), expanding the ring to open the S6 gates by pulling on the S6-RCK1 linkers (B). This hypothesis was tested by changing the length of the S6-RCK1 linkers (C). Shortening the linkers increased the open probability and lengthening the linkers decreased the open probability, consistent with the model (Niu, Qian, and Magleby, 2004).  

Magleby lab: Xiaowei Niu, Karl Magleby, Alice Holohean, Chris Shelley, Yaxia Zhang 

• Google Scholar Citations
• PubMed Citations

Selected Publications

1. Brelidze TI and Magleby KL (2005) Probing the geometry of the inner vestibule of BK channels with sugars. J. General Physiol. 126:105-121.
2. Magleby KL (2004) Modal gating of NMDA receptors. Trends Neurosci. 27(5):231-3.
3. Kalkstein JM and Magleby KL (2004) Augmentation increases vesicular release probability in the presence of masking depression at the frog neuromuscular junction. J. Neuroscience, 24:11391-11401.
4. Niu X, Qian X and Magleby KL (2004) Linker-gating ring complex as passive spring and Ca2+ -dependent machine for a voltage and Calcium-Activated Potassium Channel. Neuron 42:745-756
5. Brelidze T and Magleby KL (2003) Protons block BK channels by competitive inhibition with K+ and contribute to the limits of unitary currents at high voltages. J. Gen. Physiol. 123:305-319.
6. Qian X and Magleby KL (2003) Beta-1 subunits facilitate gating of BK channels by acting through the Ca2+, but not the Mg2+, activating mechanisms. Proc. National. Acad. Sci. USA 100:10061-10066.
7. Brelidze T, Niu X, and Magleby KL (2003) A ring of eight conserved negatively charged amino acids dobles the conductance of BK channels and prevents inward rectification. Proc. National. Acad. Sci. USA, 100:9017-9022.
8. Qian X, Nimigean CM, Niu X, Moss BL, and Magleby KL (2002) Slo1 tail domains, but not the Ca2+ bowl, are required for the beta 1 subunit to increase the apparent Ca2+ sensitivity of BK channels. J. Gen. Physiol. 120:829-843.
9. Niu X and Magleby KL (2002) Stepwise contribution of each subunit to the cooperative activation of BK channels by Ca2+. Proc. National. Acad. Sci. USA. 99:11441-11446.
10. Moss BL and Magleby KL (2001) Gating and conductance properties of BK channels are modulated by the S9-S10 tail domain of the alpha subunit. A study of mSlo1 and mSlo3 wild-type and chimeric channels. J. Gen. Physiol. 118:711-734.
11. Gil Z, Magleby KL and Silberberg SD (2001) Two-dimensional kinetic analysis suggests non-sequential gating of mechanosensitive channels in Xenopus Ooocytes. Biophysical J. 81:2082-2099.
12. Rothberg BS and Magleby KL (2001) Testing for detailed balance (microscopic reversibility) in ion channel gating. Biophysical J. 80:3025-3026. (Reviewed letter to the editor.)
13. Rothberg BS and Magleby KL (2000) Voltage and Ca2+ activation of single large-conductance Ca2+-activated K+ channels described by a two-tiered allosteric gating mechanism.  J Gen Physiol. 116(1):75-99.
14. Nimigean CM and Magleby KL (2000) Functional coupling of the beta(1) subunit to the large conductance Ca(2+)-activated K(+) channel in the absence of Ca(2+) Increased Ca(2+) sensitivity from a Ca(2+)-independent mechanism.  J Gen Physiol. 115(6):719-36.
15. Gil Z, Silberberg SD, and Magleby KL (1999) Voltage-induced membrane displacement in patch pipettes activates mechanosensitive channels. Proc. National. Acad. Sci. USA. 96:14594-14599.
16. Rothberg BS and Magleby KL (1999) Gating kinetics of single large-conductance Ca2+ activated K+ channels in high Ca2+ suggest a two-tiered allosteric gating mechanism. J. General Physiology 114:93-124.
17. Gil Z., Magleby KL, and Silberberg SD (1999) Membrane-pipette interactions underlie delayed voltage activation of mechanosensitive channels in Xenopus oocytes. Biophysical J. 76:3118-3127.
18. Moss BL, Silberberg SD, Nimigean CM, and Magleby KL (1999) Ca2+-dependent gating mechanisms for dSlo, a large-conductance Ca2+-activated K+ (BK) channel. Biophysical J. 76:3099-3117.

Curriculum Vitae

• 1966 B.S. Molecular and Genetic Biology, University of Utah
• 1970 Ph.D. Physiology and Biophysics, University of Washington, Seattle
• 1970-1971 Postdoctoral Fellow, Neuroscience, University of Washington, Seattle
• 1971-1975 Assistant Professor, Department of Physiology and Biophysics, University of Miami School of Medicine
• 1975-1980 Associate Professor, Department of Physiology and Biophysics, University of Miami School of Medicine
• 1980-present Professor , Department of Physiology and Biophysics, University of Miami School of Medicine
• 1992-present Chairman, Department of Physiology and Biophysics, University of Miami School of Medicine