Philadelphia University + Thomas Jefferson University

O'Leary, Michael

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Michael E. O'Leary, PhD

Contact Dr. O'Leary

900 Walnut Street
Philadelphia, PA 19107

(215) 503-9983

Research and Clinical Interests

Voltage-gated ion channels of primary sensory neurons

Sensory nerve fibers originate in the dorsal root ganglion and produce long branches that terminate in peripheral tissues. The termini of these sensory neurons elaborate specialized membrane bound proteins that convert mechanical, thermal, and chemical stimuli into electrical signals that are transmitted along the sensory nerve fibers back to the spinal cord. Included in these sensory nerve fibers are subsets of unmyelinated fibers that predominately respond to noxious/painful stimuli. These nociceptive nerve fibers are the initial link in the pain-sensing pathway. The research in my laboratory utilizes a combination of electrophysiology and molecular biology to investigate the mechanisms of sensory neuron transduction and the propagation of electrical signals along nociceptive nerve fibers. To do this we developed novel methodologies that permit electrical recording and genetic screening of individual sensory neurons. Quantitative analysis of the mRNA transcripts expressed in single nociceptors enables us to correlate the electrical properties with the specific proteins expressed in these neurons. Using this approach we have identified the several classes of voltage-gated ion channels that are uniquely expressed in nociceptors. Recent work indicates that these neurons exclusively express the Nav1.7, Nav1.8 and Nav1.9 sodium channel isoforms and that these channels underlie the electrical excitability of nociceptive neurons.

My laboratory utilizes state-of-art electrophysiology and molecular techniques including patch-clamp, two-electrode voltage clamp, immunofluorescence, confocal imaging, western blot, immunoprecipitation, and quantitative RT-PCR.

The long-term goal of our studies is to fully catalogue the ligand- and voltage-gated ion channels expressed in nociceptors. These findings will enhance our understanding of nociceptor function and serve as guides for designing novel strategies for treating acute and chronic pain.

Publications

Most Recent Peer-Reviewed Publications

  1. MTSET modification of D4S6 cysteines stabilize the fast inactivated state of Nav1.5 sodium channels
  2. Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury
  3. Modulation of peripheral Na+ channels and neuronal firing by n-butyl-p-aminobenzoate
  4. Differential expression of sodium channel β subunits in dorsal root ganglion sensory neurons
  5. Modulation of Kv3.4 channel N-type inactivation by protein kinase C shapes the action potential in dorsal root ganglion neurons
  6. Regulatory role of voltage-gated Na+ channel β subunits in sensory neurons
  7. Regulation of Nav1.6 and Nav1.8 peripheral nerve Na+ channels by auxiliary β-subunits
  8. Single-cell analysis of sodium channel expression in dorsal root ganglion neurons
  9. Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels
  10. Role of voltage-gated sodium, potassium and calcium channels in the development of cocaine-associated cardiac arrhythmias
  11. Lidocaine promotes the trafficking and functional expression of Na v1.8 sodium channels in mammalian cells
  12. Inhibition of the A-type K+channels of dorsal root ganglion neurons by the long-duration anesthetic butamben
  13. State-dependent trapping of flecainide in the cardiac sodium channel
  14. Closing and Inactivation Potentiate the Cocaethylene Inhibition of Cardiac Sodium Channels by Distinct Mechanisms
  15. Kv1.1 channels of dorsal root ganglion neurons are inhibited by n-butyl-p-aminobenzoate, a promising anesthetic for the treatment of chronic pain
  16. Cocaine binds to a common site on open and inactivated human heart (Nav 1.5) sodium channels
  17. Inhibition of HERG potassium channels by cocaethylene: A metabolite of cocaine and ethanol
  18. Gating properties of Nav1.7 and Nav1.8 peripheral nerve sodium channels
  19. Inhibition of human ether-a-go-go potassium channels by cocaine
  20. Characterization of the isoform-specific differences in the gating of neuronal and muscle sodium channels