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Frank HorriganDepartment: Address: One Baylor Plaza, BCM 335, Rm s430a Houston, TX 77030 Phone: 713-798-4675 Fax: 713-798-5441 Email: horrigan@bcm.edu Web: www.bcm.edu/physio/horrigan/?PMID=9057 |
Education
B.S. Physics/Biophysics University of Michigan (1984)
Ph.D. Biology Stanford University (1991)
Honors
Paul Cranefield Award, Society of General Physiologists (2007)
Elected Council Member, Society of General Physiologists (2009-2012)
Research Topic
Molecular and Biophysical Mechanisms of Ion Channel Function.
Research Description
Our research focuses on mechanisms that govern the opening and closing (gating) of ion channels. Ion channels are transmembrane proteins that transduce stimuli such as membrane voltage or ligand-binding into electrochemical signals by regulating membrane permeability. In this way channels mediate electrical and chemical signaling that are crucial to the function of nerve, muscle, and other cell types. Thus an understanding of ion channel gating has broad consequences for understanding normal cell function, disease and therapeutic mechanisms. We are particularly interested in the physical basis of channel gating, how multiple stimuli interact to determine channel activity, and how drugs regulate this process.
To transduce signals, an ion channel must contain Sensors to detect stimuli, a Gate to control the flow of ions through an ion-selective pore, and mechanisms that couple Sensors to the Gate. Sensor and Gate domains have been identified in many channels, but the mechanisms by which they communicate remain poorly understood. Therefore an important goal of our research has been to determine the functional properties and molecular basis of Sensor/Gate communication and how it is regulated.
To understand how Sensors and Gates communicate we study the large conductance Ca2+-activated K+ (BK) channel; a channel that is unique in its ability to sense both membrane voltage and intracellular calcium. BK channels play important roles in processes such as synaptic transmission and the regulation of vascular smooth muscle tone, and have been targeted therapeutically to treat conditions such as stroke, hypertension, asthma and cancer. We find that communication between voltage-sensors, Ca2+-sensors, and the channel gate can be described in terms of allosteric mechanisms. We are determining the molecular basis of these interactions. We are also studying how drugs and endogenous regulatory factors (e.g. Mg2+, Cu2+, heme and steroid hormones) affect gating processes controlled by voltage and Ca2+. Finally we are investigating the role BK channel deregulation in cell proliferation and cancer. We seek to establish a comprehensive understanding of BK channel regulation that may serve as a basis for understanding disease mechanisms and developing more effective therapeutic options.
Techniques employed in the lab include, but are not limited to, patch clamp electrophysiology, site-directed mutagenesis, the substituted cysteine accessibility method (SCAM), and computer modeling of channel gating and structure.
Selected Publications
- Gilly, W.F., M. T. Lucero, F.T. Horrigan (1990): Control of the spatial distribution of sodium channels in giant fiber lobe neurons of the squid. Neuron 5:663-674.
- Horrigan F.T., R.J. Bookman (1994): Releasable pools and the kinetics of exocytosis in adrenal chromaffin cells. Neuron 13:1119-1129.
- Horrigan F.T., J., Cui, R.W. Aldrich (1999): Allosteric voltage-gating of potassium channels I: mSlo ionic currents in the absence of Ca2+. J. Gen. Physiol. 114: 277-304.
- Horrigan F.T., R.W. Aldrich (1999): Allosteric voltage-gating of potassium channels II: mSlo channel gating charge movement in the absence of Ca2+. J. Gen. Physiol. 114: 305-336, 1999.
- Horrigan, F.T., R.W. Aldrich (2002): Coupling between Voltage Sensor Activation, Ca2+ Binding and Channel Opening in Large Conductance (BK) Potassium Channels. J. Gen. Physiol. 120: 267- 305,.
- Horrigan, F.T., S.H. Heinemann, T. Hoshi. (2005). Heme Regulates Allosteric Activation of the Slo1 BK Channel. J. Gen. Physiol.. 126:7-21.
- Ma, Z., X.J. Lou, and F.T. Horrigan. (2006). Role of charged residues in the S1-S4 voltage sensor of BK channels. J. Gen. Physiol. 127:309-328.
- Yang, H., L. Hu, J. Shi, K. Delaloye, F.T. Horrigan, and J. Cui (2007): Mg2+ mediates interaction between the voltage-sensor and cytosolic domain to activate BK channels. Proc. Natl. Acad. Sci. USA 104(46): 18270-18275.
- Horrigan, F.T., and Z. Ma (2008): Mg2+ Enhances Voltage Sensor/Gate Coupling in BK Channels. J. Gen. Physiol., 131(1): 13-32.
- Ma, Z, K.Y. Wong and F.T. Horrigan (2008): An Extracellular Cu2+ Binding Site in the Voltage Sensor of BK and Shaker Potassium Channels. J. Gen. Physiol., 131(5): 483-502.
Lab Members
Current Graduate Students
Current Post Docs
Lab Photos
Last edited on: October 14, 2009