The overall goals of Dr. Wang’s laboratory are (1) to map the local anesthetic receptor within the voltage-gated Na+ channel and (2) to identify novel drugs that may be applicable as long-acting analgesics for prolonged pain relief. Local anesthetics are clinic drugs that block action potentials in excitable membranes reversibly. The main targets of local anesthetics are voltage-gated Na+ channels, which are responsible for the generation and propagation of action potentials in excitable membranes. Prolonged nerve block by long-acting local anesthetics is desirable for alleviating postoperative pain. Local anesthetics are also used in pain management for chronic and cancer pain but their applications appear limited because of the short blocking action.
Mammalian Na+ channels contain a large α-subunit (Nav1.1-1.9) and one or two small β-subunit (β1-β4). The primary structure of the α-subunit isoform consists of four homologous domains (D1-D4) each with six transmembrane segments (S1-S6). The local anesthetic receptor has been mapped to a cluster of residues at D1S6, D3S6, and D4S6 segments encircling the inner cavity of the Na+ channel. Dr. Wang’s laboratory is working to identify the contact points of local anesthetics with the Na+ channel in order to understand how the Na+ permeation pathway is blocked by local anesthetics. Towards this goal, Dr. Wang is also collaborating with other theorists to construct an open Na+ channel model for in silico local anesthetic docking within the inner cavity. Such a model will be used to reveal and/or to confirm the contact points between local anesthetics and residues within the Na+ channel. With this model Dr. Wang’s laboratory will be able to explore whether drugs can be identified as local anesthetics by the docking exercise and later tested in animal for their duration of nerve block.
To identify novel drugs, Dr. Wang’s laboratory is working to establish stable cell lines that express robust inactivation-deficient Na+ channels. Persistent late Na+ currents are likely the culprit that induces ecotopic high-frequency discharges in injured nerve. Such high-frequency discharges have been found as the cause for neuropathic pain. Cell lines that express robust inactivation-deficient Na+ channels are therefore valuable as screening tools to identify drugs that target persistent late Na+ currents. Four cell lines have now been established in Dr. Wang’s laboratory: (1) inactivation-deficient rNav1.4-WCW mutant channels, (2) inactivation-deficient hNav1.4-CW mutant channels, (3) inactivation-deficient hNav1.7-WCW mutant channels, and (4) inactivation-deficient hNav1.5-CW mutant channels. Recent studies in Dr. Wang’s laboratory regarding local anesthetic block, the establishment of cell lines expressing inactivation-deficient Na+ channels, and the construction of the open Na+ channel model are listed below in the published form.
Ging-Kuo Wang, Ph.D. is a Biochemist at Brigham and Women's Hospital, and Principal Investigator in the Pain Reseaerch Center.
- Wang,G.K., T.Edrich, and S.Y.Wang. 2006. “Time-Dependent Block and Resurgent Tail Currents Induced by Mouse β4(154-167) Peptide in Cardiac Na+ Channels.” J Gen. Physiol 127:277-289.
- Wang,S.-Y., J.Mitchell, and G.K.Wang. 2007. “Preferential block of inactivationdeficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel.” Pain 127:73-83.
- Wang,C.F., P.Gerner, S.-Y.Wang, and G.K.Wang. 2007. “Bulleyaconitine A isolated from aconitum plant displays long-acting local anesthetic properties in vitro and in vivo.” Anesthesiology 107:82-90.
- Wang,G.K., J.Calderon, and S.Y.Wang. 2008. “State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine.” Mol. Pharmacol 73:940-948.
- Wang,G.K., J.Mitchell, and S.Y.Wang. 2008. “Block of Persistent Late Na+ Currents by Antidepressant Sertraline and Paroxetine.” J Membr. Biol. 222:79-90.
- Wang SY, Calderon J, G.K. Wang. “Block of neuronal Na+ channels by antidepressant duloxetine in a state-dependent manner.” Anesthesiology 2010; 113:655-65.